去乙酰化酶(Sirtuins)与胰岛素抵抗

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Sirtuins and Insulin Resistance

The mammalian Sirtuins (SIRT1-7) are an evolutionarily conserved family of NAD+-dependent deacylase and mono-ADP-ribosyltransferase. Sirtuins display distinct subcellular localizations and functions and are involved in cell survival, senescence, metabolism and genome stability. Among the mammalian Sirtuins, SIRT1 and SIRT6 have been thoroughly investigated and have prominent metabolic regulatory roles. Moreover, SIRT1 and SIRT6 have been implicated in obesity, insulin resistance, type 2 diabetes mellitus (T2DM), fatty liver disease and cardiovascular diseases. However, the roles of other Sirtuins are not fully understood. Recent studies have shown that these Sirtuins also play important roles in inflammation, mitochondrial dysfunction, and energy metabolism. Insulin resistance is the critical pathological trait of obesity and metabolic syndrome as well as the core defect in T2DM. Accumulating clinical and experimental animal evidence suggests the potential roles of the remaining Sirtuins in the regulation of insulin resistance through diverse biological mechanisms. In this review, we summarize recent advances in the understanding of the functions of Sirtuins in various insulin resistance-associated physiological processes, including inflammation, mitochondrial dysfunction, the insulin signaling pathway, glucose, and lipid metabolism. In addition, we highlight the important gaps that must be addressed in this field.

哺乳动物 Sirtuins (SIRT1-7)是 NAD + 依赖的脱酰化酶和单 adp- 核糖基转移酶的一个进化保守家族。去乙酰化酶具有独特的亚细胞定位和功能,参与细胞存活、衰老、新陈代谢和基因组稳定性。在哺乳动物 Sirtuins 中,SIRT1和 SIRT6已经被彻底研究,并且具有显著的代谢调控作用。此外,SIRT1和 SIRT6与肥胖、胰岛素抵抗、2型糖尿病、脂肪肝和心血管疾病有关。然而,其他 Sirtuins 的作用并没有被完全理解。最近的研究表明,这些去乙酰化酶也发挥重要作用的炎症,线粒体功能障碍和能量代谢。胰岛素抵抗是肥胖和代谢症候群的重要病理特征,也是2型糖尿病的核心缺陷。越来越多的临床和实验动物证据表明,通过不同的生物学机制,其余去乙酰化酶在调节胰岛素抵抗中的潜在作用。本文综述了去乙酰化酶在各种胰岛素抵抗相关生理过程中的作用,包括炎症、线粒体功能障碍、胰岛素信号通路、葡萄糖和脂质代谢。此外,我们强调在这一领域必须解决的重要差距。

Introduction

引言

The increasing prevalence of obesity and associated metabolic syndrome (including type 2 diabetes mellitus [T2DM], nonalcoholic fatty liver disease [NAFLD], atherosclerosis and atherosclerotic heart disease) is an increasingly severe challenge in public health (1). Insulin resistance is the critical, universal pathological feature of these diseases, especially T2DM. Insulin is a major hormone secreted by pancreatic β cells after nutrient stimulation and plays a critical role in reducing blood glucose concentration by facilitating glucose uptake by skeletal muscle and adipose tissue and inhibiting endogenous glucose production in the liver (24). Insulin resistance occurs when cells are incapable of efficiently responding to a normal dose of insulin (24). The development of insulin resistance is a multistep, complex process influenced by genetics and environments (3). Although the precise pathogenesis of insulin resistance remains incompletely understood, several mechanisms are proposed to be involved, including defects in the insulin signaling pathway, ectopic lipid accumulation, systemic inflammation, mitochondrial dysfunction, oxidative stress, and endoplasmic reticulum (ER) stress, as reviewed elsewhere (156).

肥胖及其相关代谢症候群的患病率不断上升(包括2型糖尿病、非酒精性脂肪肝、动脉粥样硬化和冠状动脉疾病) ,对公共卫生是一个越来越严峻的挑战。胰岛素抵抗是这些疾病尤其是 T2DM 的重要、普遍的病理特征。胰岛素是胰腺细胞在营养刺激后分泌的主要激素,通过促进骨骼肌和脂肪组织摄取葡萄糖和抑制肝脏内源性葡萄糖(2-4) ,在降低血糖浓度方面发挥重要作用。当细胞对正常剂量的胰岛素(2-4)不能有效地作出反应时,就会发生胰岛素抵抗。胰岛素抵抗的发生是一个受遗传和环境影响的多步骤、复杂的过程(3)。虽然胰岛素抵抗的确切发病机制尚不完全清楚,但已有几种机制被提出参与其中,包括胰岛素信号通路缺陷、异位脂质堆积、全身炎症、线粒体功能障碍、氧化应激和内质网应激等。

The mammalian Sirtuins are a family of NAD+-dependent deacetylases (7). This family consists of seven members (SIRT1-SIRT7), which share the conserved Sirtuin domain conferring NAD+-dependent deacetylase activity but have variable amino- and carboxy-terminal extensions and display distinct subcellular localization and biological functions (89). SIRT1 is mainly localized to the nucleus (10), but it shuttles between the nucleus and cytoplasm during development and in response to physiological and pathological stress (11). In contrast to SIRT1, mammalian SIRT2 is mainly localized to the cytoplasm (1012) but is also found in the nucleus (13). SIRT3, SIRT4, and SIRT5 are localized to mitochondria (1014), whereas SIRT6 and SIRT7 are found in the nucleus (10). SIRT6 is a chromatin-associated protein, and SIRT7 resides in the nucleolus (1516). Deacetylase activity was initially reported as conserved in mammalian Sirtuins, but different Sirtuins exhibit different acyl group preferences (17). Among the seven Sirtuins, SIRT4-7 exhibit weak or undetectable deacetylation activity in vitro (1018). SIRT2 reportedly possesses efficient demyristoylase activity (18). SIRT5 is reportedly an efficient NAD+-dependent protein, lysine desuccinylase and demalonylase (19), while SIRT4 and SIRT6 reportedly possess ADP-ribosyltransferase activity (2021).

哺乳动物去乙酰化酶是 NAD + 依赖的去乙酰化酶家族(7)。该家族有7个成员(SIRT1-SIRT7) ,它们具有与 NAD + 依赖性脱乙酰基酶活性相同的保守 Sirtuin 结构域,但具有可变的氨基末端和羧基末端延伸,表现出明显的亚细胞定位和生物学功能(8,9)。SIRT1主要定位于细胞核(10) ,但在发育过程中和应对生理和病理应激时,它穿梭于细胞核和细胞质之间(11)。与 SIRT1相反,哺乳动物 SIRT2主要定位于细胞质(10,12) ,但也存在于细胞核(13)。SIRT3、 SIRT4和 SIRT5定位于线粒体(10,14) ,而 SIRT6和 SIRT7定位于细胞核(10)。SIRT6是一种染色质相关蛋白,SIRT7存在于核仁中(15,16)。去乙酰化酶活性在哺乳动物 Sirtuins 中最初被报道是保守的,但不同的 Sirtuins 表现出不同的酰基偏好(17)。在七种去乙酰化酶中,SIRT4-7在体外表现出弱或无法检测到的去乙酰化活性(10,18)。据报道,SIRT2具有高效的脱肉豆蔻酸酶活性(18)。SIRT5是一个高效的 NAD + 依赖性蛋白,赖氨酸脱羧酶和脱孤核酶(19) ,而 SIRT4和 SIRT6则具有 adp- 核糖基转移酶活性(20,21)。

Mammalian Sirtuins regulate a wide variety of cellular processes, including metabolism, mitochondrial homeostasis, oxidative stress, inflammation, autophagy and apoptosis (22). Sirtuins also play important roles in aging and aging-related diseases, such as obesity, T2DM, cardiovascular disease, cancer, neurodegenerative diseases (23). SIRT1 and SIRT6 are the most extensively characterized Sirtuins. A large body of literature indicates that these two Sirtuins play an important role in metabolism, and they have also recently attracted increased attention with regard to their protective roles in maintaining insulin sensitivity, as reviewed elsewhere (2426). Compared to the metabolic roles of SIRT1 and SIRT6, the metabolic roles of other Sirtuins remain poorly understood. Here, we review the recent advances in the understanding of the roles of Sirtuins in inflammation, mitochondrial dysfunction, and oxidative stress and discuss their possible roles in insulin resistance.

哺乳动物的去乙酰化酶调节多种多样的细胞过程,包括新陈代谢、线粒体内稳态、氧化应激、炎症、自噬和凋亡。去乙酰化酶还在衰老和衰老相关疾病中发挥重要作用,如肥胖、2型糖尿病、心血管疾病、癌症、神经退行性疾病(23)。SIRT1和 SIRT6是最具特征性的 Sirtuins。大量文献表明,这两种去乙酰化酶在新陈代谢中起着重要作用,而且正如其他文献所述(24-26) ,它们在维持胰岛素敏感性方面的保护作用最近也引起了越来越多的关注。与 SIRT1和 SIRT6的代谢作用相比,其他 Sirtuins 的代谢作用仍然知之甚少。在这里,我们回顾了关于 Sirtuins 在炎症、线粒体功能障碍和氧化应激中的作用的最新进展,并讨论了它们在胰岛素抵抗中的可能作用。

Sirtuins in Inflammation

炎症中的去乙酰化酶

Obesity-induced chronic, low-grade inflammation is one of the most important contributors to the pathogenesis of insulin resistance (2729). Adipose tissue is not only an insulin-targeting organ for lipid metabolism but also an endocrine organ that secretes hormones, cytokines, and chemokines to influence insulin sensitivity. For instance, adipocytes secrete adipokines, such as leptin and adiponectin, to promote insulin sensitivity (3031), and resistin and retinol-binding protein 4 (RBP4) to impair insulin sensitivity (3233). Importantly, adipose tissue is a critical initiator of the inflammatory response to obesity (28). In obesity, metabolism and gene expression of adipocytes change, resulting in increased lipolysis of adipocytes, the release of free fatty acids and proinflammatory cytokines and activation of M1 macrophages (2729). M1 macrophages produce a large number of proinflammatory mediators, such as TNF-α, IL-1β, and resistin, that act on adipocytes to induce an insulin-resistant state and activate inflammatory pathways in insulin-targeting cells. Ultimately, ectopic lipid deposition and increased expression of inflammatory mediators in the liver and skeletal muscle lead to impaired insulin signaling and exacerbate systemic insulin resistance (29). Signals from all the proinflammatory mediators converge on inflammatory signaling pathways, including jun-n-terminal kinase (JNK) and inhibitor of nuclear factor κB (NF-κB) kinase (IKK) (273435). Inhibition of insulin receptor downstream signaling is the primary mechanism for inflammation-induced insulin resistance (27). Activated JNK or IKK can phosphorylate the insulin receptor (IR) and insulin receptor substrate (IRS) proteins and decrease their tyrosine phosphorylation, thus leading to decreased activation of PI3-kinase and Akt and resistance to the metabolic actions of insulin (3436). In addition, activation of the JNK and IKK pathways can induce the production of inflammatory mediators, while the Sirtuin family plays essential roles in inflammation, which comprehensively contributes to insulin resistance.

肥胖引起的慢性轻度炎症是胰岛素抵抗发病机制中最重要的因素之一(27-29)。脂肪组织不仅是脂质代谢的胰岛素靶向器官,也是分泌激素、细胞因子和趋化因子来影响胰岛素敏感性的内分泌器官。例如,脂肪细胞分泌脂肪因子,如瘦素和脂联素,以提高胰岛素敏感性(30,31) ,抵抗素和视黄醇结合蛋白4(RBP4) ,以削弱胰岛素敏感性(32,33)。重要的是,脂肪组织是肥胖症炎症反应的关键引发者(28)。肥胖时,脂肪细胞的代谢和基因表达发生改变,导致脂肪细胞脂解增加,游离脂肪酸和促炎细胞因子释放,M1巨噬细胞(27-29)活化。M1巨噬细胞产生大量促炎症介质,如 tnf-、 il-1和抵抗素,这些介质作用于脂肪细胞,诱导胰岛素抵抗状态,激活胰岛素靶向细胞的炎症通路。最终,肝脏和骨骼肌中异位脂质沉积和炎症介质表达增加导致胰岛素信号受损,并加剧全身胰岛素抵抗(29)。来自所有炎症介质的信号汇聚于炎症信号通路,包括 jun-n 末端激酶(JNK)和核因子 b 抑制剂(nf- b)激酶(IKK)(27,34,35)。抑制胰岛素受体下游信号传导是炎症诱导的胰岛素抵抗的主要机制。活化的 JNK 或 IKK 可以磷酸化胰岛素受体蛋白(IR)和胰岛素受体底物(IRS) ,减少其酪氨酸磷酸化,从而导致 pi3激酶和 Akt 的活性降低,以及对胰岛素代谢活动的抵抗(34,36)。此外,JNK 和 IKK 通路的激活可以诱导炎症介质的产生,而 Sirtuin 家族在炎症中扮演重要角色,综合地促进胰岛素抵抗。

Inflammatory Transcriptional Factor

炎症转录因子

NF-κB is a key transcriptional factor that mediates the expression of multiple inflammatory factors, including TNF-α, IL-1β, and IL-6. The acetylation of NF-κB promotes its nuclear translocation and activation. SIRT1 has been demonstrated to repress inflammation in multiple tissues and cells (3740). In particular, SIRT1 suppresses inflammation in both adipocytes (3941) and macrophages (42), which leads to a reduction of adipose tissue inflammation. SIRT1 deacetylates p65 subunit of NF-κB at lysine 310 (K310) and inhibits the transcriptional activity of NF-κB (43). Moreover, SIRT1 interacts with transducing-like enhancer of split 1 (TLE1), a co-repressor of NF-κB, to inhibit NF-κB-mediated transcription (44). In addition, SIRT1 deacetylates activator protein-1 (AP-1) to reduce the expression of COX-2 in macrophages and deacetylates p53 to repress macrophage activation (4546). Similar to SIRT1, SIRT2 also binds to NF-κB and mediates the deacetylation of NF-κB subunit p65 at K310, which leads to the inhibition of the expression of NF-κB target inflammatory genes in fibroblasts, macrophages and microglial cells (4749). SIRT2-mediated inhibition of NF-κB and inflammation contributes to its anti-inflammatory function in an experimental colitis mouse model (49), neuroinflammation (485051), collagen-induced arthritis (52), and microvascular inflammation in ob/ob septic mice (53). In addition to SIRT2, SIRT4 can regulate the activation of NF-κB. SIRT4 has been shown to negatively regulate cigarette smoke extract (CSE)-induced NF-κB activation by inhibiting the degradation of IκBα and inhibiting NF-κB target gene expression, including the proinflammatory cytokines IL-1β, TNF-α, and IL-6, resulting in inhibition of CSE-induced mononuclear cell adhesion to human pulmonary microvascular endothelial cells (54). SIRT4 can prevent NF-κB nuclear translocation as well as the transcriptional activity of NF-κB, thereby suppressing inflammation in human umbilical vein endothelial cells (55). Interestingly, the role of SIRT5 in inflammation is controversial. Recently, Qin and colleagues showed that SIRT5 deficiency decreased toll-like receptor (TLR)-triggered inflammation in both acute and immunosuppressive phases of sepsis (56). Mechanistically, SIRT5 competes with SIRT2 to interact with NF-κB p65 in a deacetylase activity-independent manner and thus blocks the deacetylation of p65 by SIRT2, which consequently leads to the activation of the NF-κB pathway and induction of its downstream cytokines in macrophages (56). However, Wang and colleagues found that SIRT5 desuccinylates and actives pyruvate kinase isoform M2 (PKM2) by promoting its dimerization and nuclear accumulation, thereby decreasing proinflammatory cytokine IL-1β production in LPS-activated macrophages (57). As hyperproduction of IL-1β contributes to increased susceptibility to inflammatory bowel disease, Sirt5-deficient mice are more susceptible to dextran sulfate sodium (DSS)-induced colitis (57). Interestingly, Sirt6 deficient mice display increased expression of NF-κB-dependent genes in multiple tissues (58). Sirt6 deletion increases inflammation in the mice adipose tissue and promotes HFD-induced insulin resistance (5960). Mechanistically, SIRT6 binds to the NF-κB subunit RelA and deacetylates histone H3 lysine 9 (H3K9) at NF-κB target gene promoters, which leads to a reduction of NF-κB target gene expression (58). These findings suggest that the Sirtuins target inflammatory transcriptional factors (e.g., NF-κB and AP1) directly or indirectly to contribute to insulin resistance comprehensively.

Nf- b 是一个关键的转录因子,介导多种炎症因子的表达,包括 tnf-,il-1,和 IL-6。Nf- b 的乙酰化促进其核移位和活化。SIRT1可以抑制多种组织和细胞的炎症反应(37-40)。尤其是,SIRT1抑制脂肪细胞(39,41)和巨噬细胞(42)的炎症,从而减少脂肪组织的炎症。SIRT1在赖氨酸310(K310)位点脱乙酰化 nf- b 的 p65亚基,抑制 nf- b 的转录活性。此外,SIRT1还与 nf- b 的共抑制子分裂1(TLE1)的转导样增强子相互作用,抑制 nf- 介导的转录(44)。此外,SIRT1去乙酰化激活蛋白 -1(AP-1)抑制巨噬细胞 COX-2的表达,去乙酰化 p53抑制巨噬细胞活化(45,46)。与 SIRT1相似,SIRT2也与 nf- b 结合,并在 K310介导 nf- b 亚基 p65的去乙酰化,从而抑制成纤维细胞、巨噬细胞和小胶质细胞 nf- b 靶向炎症基因的表达(47-49)。Sirt2介导的 nf- b 和炎症的抑制有助于其抗炎功能的实验性结肠炎小鼠模型(49) ,神经炎症(48,50,51) ,胶原诱导的关节炎(52) ,和微血管炎症的 ob/ob 脓毒症小鼠(53)。除 SIRT2外,SIRT4还可调节 nf- b 的激活。SIRT4通过抑制 i b 的降解和 nf- b 靶基因的表达,包括促炎细胞因子 il-1、 tnfα 和 IL-6的表达,对 CSE 诱导的单核细胞与人肺微血管内皮细胞(54)的粘附具有负性调节作用。SIRT4能阻止 nf- b 核移位和 nf- b 的转录活性,从而抑制人脐静脉内皮细胞的炎症反应(55)。有趣的是,SIRT5在炎症中的作用是有争议的。最近,秦和他的同事们发现 SIRT5缺乏可以降低引发脓毒症急性期和免疫抑制期的炎症 Toll样受体。机制上,SIRT5与 SIRT2竞争,以去乙酰化酶活性无关的方式与 nf- b p65相互作用,从而阻断 SIRT2对 p65的去乙酰化,从而导致 nf- b 通路的激活和巨噬细胞下游细胞因子的诱导(56)。然而,Wang 和他的同事发现 SIRT5通过促进丙酮酸激酶 m 2的二聚化和核聚集,从而减少 lps 激活的巨噬细胞产生促炎性细胞因子的 il-1。由于 il-1的过度产生增加了对炎症性肠病的敏感性,sirt5缺陷小鼠更容易感染葡聚糖硫酸钠(DSS)诱导的结肠炎(57)。有趣的是,Sirt6基因缺陷小鼠在多种组织中显示出 nf- 依赖性基因表达的增加(58)。Sirt6缺失增加小鼠脂肪组织的炎症,并促进 hfd 诱导的胰岛素抵抗(59,60)。机制上,SIRT6与 nf- b 亚基 RelA 结合,并在 nf- b 靶基因启动子处去乙酰化组蛋白 H3赖氨酸9(H3K9) ,导致 nf- b 靶基因表达减少(58)。这些发现提示 Sirtuins 直接或间接地靶向炎症转录因子(如 nf- b 和 AP1) ,从而全面地促进胰岛素抵抗。

Inflammasome

The anti-inflammatory role of Sirtuins involves other mechanisms. The Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex that orchestrates the innate immune responses of macrophages by controlling the activation of caspase-1 and the release of the proinflammatory cytokines IL-1β and IL-18 (6163). Obesity-related inflammation is partly mediated by the NLRP3 inflammasome, and NLRP3 activation exacerbates obesity-linked diseases (6465). Resveratrol, a SIRT1 activator, inhibits ionizing irradiation-induced inflammation in mesenchymal stem cells via suppressing NLRP3 inflammasome activation (66). In a murine model of sepsis, Sirt1 deletion results in increasing lung inflammasome activation and inflammatory lung injury (67). A recent study demonstrated that silybin prevents NLRP3 inflammasome activation during NAFLD through SIRT2 (68). However, further studies are needed to clarify the mechanism underlying SIRT2-mediated regulation of NLRP3 inflammasome activity. In a human fasting/refeeding study, Traba and colleagues observed that fasting leads to a reduction in NLRP3 inflammasome activation (69). SIRT3 deletion in a human macrophage line increases NLRP3 inflammasome activation, accompanied by excessive mitochondrial ROS production (69). Pharmacologic and genetic SIRT3 activation enhances mitochondrial function and suppresses NLRP3 activity in THP-1 monocyte cells and in leukocytes extracted from healthy volunteers and from refeeding individuals (69). The authors concluded that nutrient levels regulate the NLRP3 inflammasome partly through SIRT3-mediated mitochondrial homeostatic control. Similarly, Chen et al. reported that trimethylamine-N-oxide (TMAO) increases ROS production by inhibiting the SIRT3-SOD2-mitochondrial signaling pathway, which leads to NLRP3 inflammasome activation and consequently promotes vascular inflammation (70). Defective autophagy in monocytes or macrophages might result in NLRP3 inflammasome activation and cause vascular metabolic inflammation (7173). Acetylation of ATG5, an autophagy-related protein, inhibits autophagosome maturation and induces NLRP3 inflammasome activation (74). Recently, Liu and colleagues demonstrated that SIRT3 binds with ATG5 and deacetylates it, while SIRT3-deficient macrophages display impaired autophagy, leading to accelerated NLRP3 inflammasome activation and endothelial dysfunction (73). These studies suggest that SIRT3 may inhibit NLRP3 inflammasome activation by regulating mitochondrial function, ROS production, and autophagy. As SIRT2 has also been shown to regulate NLRP3 inflammasome activation (68), the potential synergistic effect on regulation of NLRP3 inflammasome activation between SIRT3 and SIRT2 needs further study. Previous studies have highlighted the anti-inflammatory role of SIRT3 in obesity-related diseases, including insulin resistance. The function of SIRT3 in inflammasome regulation largely depends on SIRT3-mediated activation of MnSOD and suppression of oxidative stress. These findings implicate that the SIRT1-SIRT3 indirectly regulate the activation of the NLRP3 inflammasome, which may be involved in the modulation of insulin resistance. However, whether Sirtuins directly regulate inflammasome remains unknown.

Sirtuins 的抗炎作用涉及到其他机制。结瘤样受体家族,pyrin 结构域含3(NLRP3)炎性体是一个蛋白质复合体,通过调节 caspase-1的激活和释放促炎细胞因子 il-1和 IL-18(61-63)来协调巨噬细胞的天然免疫反应。与肥胖相关的炎症部分是由 NLRP3炎症体介导的,而 NLRP3的激活加重了与肥胖相关的疾病(64,65)。白藜芦醇是 SIRT1激活剂,通过抑制 NLRP3炎症体激活抑制电离辐射诱导的间充质干细胞炎症反应(66)。在脓毒症小鼠模型中,Sirt1缺失导致肺炎性蛋白质激活增加和炎症性肺损伤(67)。最近的一项研究表明,水飞蓟宾通过 SIRT2(68)阻止 NLRP3在 NAFLD 中的炎症体激活。然而,还需要进一步的研究来阐明 sirt2介导的 NLRP3炎症活性调节的机制。在一项人类禁食/再喂养的研究中,Traba 和同事观察到禁食导致 NLRP3炎症激活的减少(69)。人类巨噬细胞系 SIRT3缺失增加了 NLRP3炎症体的活化,伴随着线粒体活性氧的过度产生(69)。药理学和遗传学上 SIRT3激活增强线粒体功能,抑制从健康志愿者和重新喂养个体中提取的 THP-1单核细胞和白细胞的 NLRP3活性(69)。作者认为营养素水平部分通过 sirt3介导的线粒体内环境稳定调节 NLRP3炎症体。类似的,Chen 等人报告说,氧化三甲胺(TMAO)通过抑制 sirt3-sod2-mtdna 信号通路来增加 ROS 的产生,从而导致 NLRP3炎症体的激活,从而促进血管炎症。单核细胞或巨噬细胞自噬功能缺陷可能导致 NLRP3炎症小体激活,引起血管代谢性炎症(71-73)。自噬相关蛋白 ATG5的乙酰化抑制自噬体成熟并诱导 NLRP3的激活(74)。最近,Liu 和他的同事证明 SIRT3与 ATG5结合并去乙酰化,而 SIRT3缺陷的巨噬细胞表现出受损的自噬,导致 NLRP3激活和内皮功能障碍(73)。这些研究表明,SIRT3可能通过调节线粒体功能、活性氧产生和自噬来抑制 NLRP3炎症体的激活。由于 SIRT2还可以调节 NLRP3的炎症体激活(68) ,因此 SIRT3与 SIRT2之间可能存在的协同调节 NLRP3炎症体激活的作用有待进一步研究。先前的研究已经强调了 SIRT3在肥胖相关疾病中的抗炎作用,包括胰岛素抵抗。SIRT3在炎症体调节中的作用很大程度上取决于 SIRT3介导的 MnSOD 的激活和氧化应激的抑制。这些结果提示 SIRT1-SIRT3间接调节 NLRP3炎症体的激活,可能参与了胰岛素抵抗的调节。然而,Sirtuins 是否直接调节炎症体还不清楚。

Sirtuins, Inflammation and Insulin Resistance

去乙酰化酶、炎症与胰岛素抵抗

The roles of Sirtuins in inflammation significantly contribute to their functions during insulin resistance. For instance, activation of SIRT1 leads to the repression of JNK and IKK inflammatory pathways greatly and subsequently improves glucose tolerance, reduced hyperinsulinemia, and enhanced systemic insulin sensitivity (40). SIRT1 also controls the inflammatory status of macrophages and T lymphocytes to regulate the metabolism (insulin sensitivity) and inflammation of adipose tissues in obese mice (417577). In addition, SIRT6 is important for macrophage activation and TNFα production (78). Myeloid Sirt6 deficiency causes insulin resistance in HFD–fed mice by eliciting macrophage polarization toward an M1 phenotype (79), and facilitates the development of HFD-induced atherosclerosis (80). Deletion of Sirt6 in T cells or myeloid-derived cells is sufficient to induce liver inflammation and fibrosis (81). Interestingly, SIRT1 and SIRT6 can coordinate a switch from glucose to fatty acid oxidation during the acute inflammatory response (82). Therefore, Sirtuins not only regulate the inflammatory pathways within the target cells (e.g., hepatocytes, skeletal muscle cells, adipocytes) to affect their insulin sensitivity but also regulate inflammatory cells infiltrated in the organs, where the Sirtuins respond to inflammatory and metabolic insults and subsequently regulate insulin sensitivity and disease by targeting inflammatory cell activation and differentiation. Notably, the Sirtuins may also cooperate in diverse types of cells or within the same type of cell during inflammation-associated insulin resistance.

去乙酰化酶在炎症中的作用在胰岛素抵抗中起重要作用。例如,SIRT1的激活导致 JNK 和 IKK 炎症通路的极大抑制,进而提高葡萄糖耐量,降低高胰岛素血症,并增强全身胰岛素敏感性(40)。SIRT1还控制巨噬细胞和 t 淋巴细胞的炎症状态,以调节肥胖小鼠脂肪组织的代谢(胰岛素敏感性)和炎症。此外,SIRT6对巨噬细胞活化和 tnf 的产生也很重要(78)。Myeloid Sirt6缺乏通过诱导小鼠巨噬细胞向 M1表型分化而引起 HFD 小鼠的胰岛素抵抗(79) ,并促进 HFD 诱导的动脉粥样硬化(80)的发展。在 t 细胞或髓样细胞中缺失 Sirt6足以诱导肝脏炎症和纤维化(81)。有趣的是,SIRT1和 SIRT6在急性炎症反应过程中可以协调从葡萄糖到脂肪酸氧化的转换。因此,Sirtuins 不仅调节目标细胞(如肝细胞、骨骼肌细胞、脂肪细胞)内的炎症通路,影响胰岛素敏感性,而且调节器官内的炎症细胞,这些炎症细胞对炎症和代谢损伤作出反应,并通过靶向炎症细胞的活化和分化来调节胰岛素敏感性和疾病。值得注意的是,Sirtuins 也可以在炎症相关的胰岛素抵抗期间在不同类型的细胞或同一类型的细胞中进行合作。

Sirtuins in Mitochondrial Dysfunction

去乙酰化酶与线粒体功能障碍

Mitochondria are the primary site for ATP generation and ROS production. Mitochondrial dysfunction results in decreased ATP production, increased ROS production and accumulated mitochondrial DNA damage, which contribute to insulin resistance (5). Cells eliminate ROS by expressing endogenous antioxidant enzymes, including manganese superoxide dismutase (MnSOD), catalase, glutathione peroxidase (GPX) and glutathione reductase (GRx) (8384). An imbalance between the production of ROS and antioxidant enzymes leads to oxidative stress, which has been implicated in the pathogenesis of insulin resistance, obesity, and diabetes (185).

线粒体是 ATP 生成和活性氧产生的主要场所。线粒体功能障碍导致 ATP 产生减少,ROS 产生增加,线粒体脱氧核糖核酸损伤积累,这些都有助于胰岛素抵抗。细胞通过表达内源性抗氧化酶来清除活性氧,包括锰超氧化物歧化酶(MnSOD)、过氧化氢酶、谷胱甘肽过氧化物酶和谷胱甘肽还原酶(GRx)(83,84)。活性氧和抗氧化酶的产生不平衡导致氧化应激,这与胰岛素抵抗、肥胖和糖尿病的发病机制有关。

SIRT1

There are fewer mitochondria in muscles of T2DM patients than those of insulin-sensitive individuals (86). Marked reduction of oxidative phosphorylation in the mitochondria can be detected in the liver and skeletal muscle of T2DM patients and insulin-resistant individuals (8788). Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a transcriptional coactivator that regulates mitochondrial biogenesis and respiration (8990). SIRT1 has been shown to deacetylate PGC-1α at several lysine residues and regulates PGC-1α activity, which activates the transcription of genes involved in mitochondrial biogenesis (91). SIRT1 activator resveratrol promotes PGC-1α activity and increases the number of mitochondria in muscle cells, which improves mitochondrial function and protects mice against diet-induced obesity and insulin resistance (92). In addition to mitochondria biogenesis, SIRT1 regulates mitochondrial function through clearance of damaged mitochondria (93). Mechanistically, SIRT1 binds to and deacetylates autophagy regulators (including ATG5, ATG7, and ATG8) to induce mitochondria autophagy or mitophagy (93). SIRT1-mediated deacetylation of FoxO1 and FoxO3a is also known to induce the expression of autophagy pathway components (9495). Accumulating evidence has shown that SIRT1 safeguards cells from oxidative stress. SIRT1 reduces ros production by deacetylating and activating FoxO3a to upregulate expression of MnSOD and catalase (9596). SIRT1 promotes the transcriptional activity of Nuclear factor (erythroid-derived 2)-like 2 (NRF2) by deacetylating it and upregulates the expression of NRF2 target antioxidant genes, including MnSOD, catalase, glutathione, and heme oxygenase-1 (HO-1) (97).

2型糖尿病患者的肌肉线粒体数量少于胰岛素敏感者(86)。在2型糖尿病患者和胰岛素抵抗个体的肝脏和骨骼肌中可以检测到线粒体氧化磷酸化的显著减少。过氧化物酶体增殖物活化受体γ 辅激活因子1-alpha (pgc-1)是调节线粒体生物发生和呼吸的转录辅激活因子(89,90)。SIRT1能在几个赖氨酸残基上去乙酰化 pgc-1,调节 pgc-1的活性,激活线粒体生物发生相关基因的转录(91)。SIRT1激活剂白藜芦醇促进 pgc-1活性,增加肌细胞线粒体数量,改善线粒体功能,保护小鼠免受饮食诱导的肥胖和胰岛素抵抗(92)。除了线粒体生物合成,SIRT1还通过清除受损的线粒体来调节线粒体功能。机制上,SIRT1结合并去乙酰化自噬调节因子(包括 ATG5、 ATG7和 ATG8)来诱导线粒体自噬或吞噬。Sirt1介导的 FoxO1和 FoxO3a 的去乙酰化作用也可以诱导自噬途径成分的表达(94,95)。越来越多的证据表明,SIRT1保护来自氧化应激的细胞。SIRT1通过去乙酰化和活化 FoxO3a 上调 MnSOD 和过氧化氢酶(95,96)的表达来减少活性氧的产生。SIRT1通过去乙酰化促进核因子2样(NRF2)的转录活性,并上调 NRF2靶抗氧化基因(包括 MnSOD、过氧化氢酶、谷胱甘肽和血红素氧合酶 -1(HO-1))的表达。

SIRT2

Oxidative stress increases SIRT2 expression in vivo and in vitro (9899). SIRT2 can bind to FoxO3a and deacetylate it, leading to an increase in FoxO3a transcriptional activity, upregulation of the expression of FoxO target genes such as MnSOD, Bim, and p27Kip1, and a consequent decrease in ROS generation (98). Nicotinamide adenine dinucleotide phosphate (NADPH) is a functionally important metabolite that is required to generate the reduced form of glutathione (GSH) to maintain cellular redox potential. In response to oxidative stimuli, SIRT2 deacetylates and activates glucose 6-phosphate dehydrogenase (G6PD), a key enzyme in the pentose phosphate pathway (PPP), resulting in increased cytosolic NADPH to attenuate oxidative damage (100). Similarly, oxidative stress increases the glycolytic enzyme phosphoglycerate mutase (PGAM)-SIRT2 interaction, leading to deacetylation and activation of PGAM, which increases the cellular NADPH level to counteract oxidative damage (101). Lysine 4-oxononanoylation (4-ONylation) is a newly discovered histone posttranslational modification that disrupts the interaction between histone H3 and DNA, thereby preventing nucleosome assembly under oxidative stress (102). SIRT2 was reported to remove the 4-oxononanoyl (4-ONyl) lysine groups on histones and attenuate the negative impact of protein 4-ONylation caused by oxidative stress (103). This study provides novel evidence that SIRT2 may exert antioxidation effects through epigenetic modification. Oxidative stress is not completely caused by mitochondria, and whether SIRT2 can influence oxidative stress by regulating mitochondrial function is unclear.

氧化应激增加 SIRT2在体内和体外的表达(98,99)。SIRT2能与 FoxO3a 结合并脱乙酰化,导致 FoxO3a 转录活性增加,FoxO3a 靶基因如 MnSOD、 Bim 和 p27Kip1表达上调,从而导致 ROS 产生减少(98)。烟酰胺腺嘌呤二核苷酸磷酸是一种重要的功能性代谢产物,能产生还原型谷胱甘肽以维持细胞的氧化还原电位。在对氧化刺激的反应中,SIRT2去乙酰化并激活葡萄糖-6-磷酸脱氢酶(G6PD) ,一种在磷酸戊糖途径中的关键酶,导致增加细胞溶质 NADPH 以减轻氧化损伤(100)。类似地,氧化应激增加了糖酵解酶磷酸甘油酸突变酶(PGAM)-SIRT2的相互作用,导致 PGAM 的去乙酰化和活化,增加了细胞 NADPH 水平以抵消氧化损伤。赖氨酸4-羰基化(4-onanoylation,4-ONylation)是一种新发现的组蛋白翻译后修饰,它破坏了组蛋白 h 3和 DNA 之间的相互作用,从而阻止了氧化应激(102)下的核小体组装。据报道,SIRT2去除了组蛋白上的4- 羰基赖氨酸基团,并减轻了氧化应激(103)引起的蛋白质4-羰基化的负面影响。本研究为 SIRT2可能通过表观遗传修饰发挥抗氧化作用提供了新的证据。氧化应激并非完全由线粒体引起,SIRT2是否能通过调节线粒体功能影响氧化应激还不清楚。

Interestingly, a recent work by Liu and colleagues observed that SIRT2 can localize to the inner mitochondrial membrane of mouse central nervous system cells and that the acetylation of several metabolic mitochondrial proteins is altered in Sirt2-deficient mice. In mice, deletion of Sirt2 causes mitochondrial morphological changes, increases oxidative stress and decreases ATP production in MEFs and brain tissues (104), indicating that SIRT2 may deacetylate antioxidant enzymes in the mitochondria directly.

有趣的是,Liu 和他的同事最近的一项研究发现 SIRT2可以定位于小鼠中枢神经系统细胞的线粒体内膜,而且在 SIRT2缺陷的小鼠中,几种代谢性线粒体蛋白质的乙酰化发生了改变。在小鼠中,SIRT2基因的缺失导致线粒体形态学变化,增加 MEFs 和脑组织中的 ATP 氧化应激,降低 ATP 产量,这表明 SIRT2可能直接在线粒体中去乙酰化抗氧化酶。

SIRT3

SIRT3, a central mitochondrial deacetylase, deacetylates, and activates mitochondrial enzymes to regulate mitochondrial metabolism, oxidative stress, cell survival, and longevity (105). SIRT3 has been shown to play a pivotal role in maintaining mitochondrial function and ROS homeostasis. For example, SIRT3 deacetylates complex I and complex II of the electron transport chain to promote electron transport and regulate energy homeostasis (106107). SIRT3 deacetylates cyclophilin D (CypD), the regulatory component of the mitochondrial permeability transition pore (mPTP), preventing opening of the mPTP and mitochondrial dysfunction (108). SIRT3 binds to and deacetylates 8-oxoguanine-DNA glycosylase 1 (OGG1), a DNA repair enzyme that excises 7,8-dihydro-8-oxoguanine from the damaged genome, resulting in the repair of mitochondrial DNA (mtDNA) damage, protection of mitochondrial integrity, defense against mitochondrial dysfunction and prevention of stress-induced cellular apoptosis (109). In contrast, Sirt3 deficiency has been linked to increased ROS production (110111). The antioxidant action of SIRT3 involves MnSOD and mitochondrial isocitrate dehydrogenase 2 (IDH2). SIRT3 has been shown to block cardiac hypertrophy by deacetylating FOXO3a and upregulating the expression of FOXO3a target genes such as MnSOD and catalase, decreasing ROS generation (112). Notably, the antioxidative action of SIRT3 may also be attributed to its direct deacetylation and promotion of the enzyme activity of MnSOD. SIRT3 deacetylates two critical lysine residues (K53 and K89) of MnSOD that promote MnSOD antioxidation activity, thereby reducing cellular ROS (113). Direct deacetylation of lysine residues, including K68 and K122 by SIRT3, also increases the enzyme activity of MnSOD and decreases ROS production (114115). In addition to MnSOD, SIRT3 directly deacetylates and activates mitochondrial IDH2, which results in increased NADPH levels and an increased ratio of reduced to oxidized GSH in mitochondria, thus protecting cells from oxidative stress-induced damage (110116). These studies suggest that SIRT3 activity is necessary to prevent mitochondrial dysfunction and reduce oxidative stress.

3,一个中央线粒体去乙酰化酶,去乙酰化,并激活线粒体酶来调节线粒体新陈代谢,氧化应激,细胞存活和寿命(105)。SIRT3已被证明在维持线粒体功能和 ROS 稳态中发挥关键作用。例如,SIRT3脱乙酰化复合物 i 和电子传递链的复合物 II,以促进电子传递和调节能量稳态(106,107)。SIRT3脱乙酰化环亲水素 d (CypD) ,线粒体通透性转换孔(mPTP)的调节成分,防止 mPTP 的开放和线粒体功能障碍(108)。SIRT3结合并去乙酰化8- 氧鸟嘌呤-DNA 糖基化酶1(OGG1) ,这是一种 DNA 修复酶,能从受损基因组中切除7,8- 二氢 -8- 氧鸟嘌呤,导致线粒体损伤修复、线粒体完整性保护、防御线粒体功能障碍和防止应激诱导的细胞凋亡(109)。相比之下,Sirt3缺乏与活性氧增加有关(110,111)。SIRT3的抗氧化作用涉及 MnSOD 和线粒体异柠檬酸脱氢酶2(IDH2)。SIRT3通过去乙酰化 FOXO3a 和上调 FOXO3a 靶基因如 MnSOD 和过氧化氢酶的表达,抑制心肌肥大,降低 ROS 的产生(112)。SIRT3的抗氧化作用可能与其直接脱乙酰和促进 MnSOD 酶活性有关。SIRT3去乙酰化 MnSOD 的两个关键赖氨酸残基(K53和 K89) ,促进 MnSOD 的抗氧化活性,从而减少细胞活性氧(113)。直接脱乙酰化的赖氨酸残基,包括 K68和 K122的 SIRT3,也增加了 MnSOD 的酶活性,降低了活性氧产生(114,115)。除了 MnSOD 之外,SIRT3还直接去乙酰化并激活线粒体 IDH2,从而导致线粒体 NADPH 水平升高,并增加线粒体中 GSH 氧化还原的比例,从而保护细胞免受氧化应激引起的损伤(110,116)。这些研究表明,SIRT3的活性是必要的,以防止线粒体功能障碍和减少氧化应激。

SIRT4

SIRT4 functions as an efficient mitochondrial ADP-ribosyl transferase that negatively impacts gene expression and various metabolic processes in mitochondria. Our previous work demonstrated that SIRT4 promotes angiotensin II-induced development of cardiac hypertrophy by inhibiting the interaction of SIRT3 and MnSOD, which increases MnSOD acetylation levels, decreases its activity and leads to elevated ROS accumulation (117). SIRT4 may play a role different from that of SIRT3 in regulating mitochondrial function and oxidative stress. Sirt4 deficiency in vivo and in vitro increases the expression of genes involved in fatty acid β-oxidation and oxidative phosphorylation, thus enhancing fatty acid oxidation and mitochondrial respiration in liver and muscle (118119). SIRT4 increases stress-induced mitochondrial ROS production and interacts with the long form of GTPase optic atrophy 1 (L-OPA1) to promote mitochondrial fusion, thereby inhibiting mitophagy and decreasing the removal of dysfunctional mitochondria (120).

SIRT4是一种高效的线粒体 adp- 核糖转移酶,负面影响线粒体的基因表达和各种代谢过程。我们的前期工作表明,SIRT4通过抑制 SIRT3和 MnSOD 的相互作用促进血管紧张素 ii 诱导的心肌肥大,增加 MnSOD 乙酰化水平,降低其活性,导致 ROS 积累增加(117)。与 SIRT3不同,SIRT4可能在调节线粒体功能和氧化应激方面发挥不同的作用。体内和体外 Sirt4缺乏增加了与脂肪酸氧化和氧化磷酸化相关的基因的表达,从而增强了肝脏和肌肉中的脂肪酸氧化和线粒体呼吸(118,119)。SIRT4增加应激诱导的线粒体活性氧的产生,并与长形的 GTPase 视神经萎缩1(L-OPA1)相互作用,促进线粒体融合,从而抑制吞噬功能,减少功能障碍的线粒体的去除(120)。

SIRT5

SIRT5 functions to deacetylate, demalonylate, and desuccinylate multiple proteins in mitochondria (19). SIRT5 is involved in the regulation of mitochondrial fatty acid β-oxidation, the urea cycle, and cellular respiration (84121). SIRT5 binds to, desuccinylates and activates copper-zinc superoxide dismutase 1 (SOD1) to eliminate ROS (122). Moreover, SIRT5 desuccinylates IDH2 and deglutarylates G6PD, thus activating both NADPH-producing enzymes to scavenge ROS (123). SIRT5 also binds, desuccinylates and inhibits the activity of the glycolysis enzyme PKM2, which facilitates the diversion of glucose metabolites into the pentose phosphate shunt and then produces sufficient NADPH to eliminate ROS (123). Interestingly, a very recent study showed that SIRT5 is present in peroxisomes and can bind, desuccinylate and inhibit ACOX1, the first and rate-limiting enzyme in fatty acid β-oxidation and a major producer of H2O2, attenuating peroxisome-induced oxidative stress (124).

SIRT5对线粒体中的去乙酰化、去甲醛化和去琥珀酸多重蛋白起作用(19)。SIRT5参与调节线粒体脂肪酸氧化、尿素循环和唿吸作用(84,121)。SIRT5结合、脱 uccinylate 并激活超氧化物歧化酶1(SOD1)以消除 ROS (122)。此外,SIRT5脱 uccinylate IDH2和 deglutarylate G6PD,从而激活两个 nadph 产生酶清除活性氧(123)。SIRT5还与糖酵解酶 PKM2结合、脱 uccinylates 并抑制其活性,后者促进葡萄糖代谢物进入戊糖磷酸分流,然后产生足够的 NADPH 来清除 ROS (123)。有趣的是,最近的一项研究表明,SIRT5存在于过氧化物酶体中,可以结合、脱去 uccinlate 和抑制 ACOX1,这是脂肪酸氧化中的第一个限速酶,也是 H2O2的主要产生者,可以减弱过氧化物酶体诱导的氧化应激(124)。

SIRT6

SIRT6 plays an important role in DNA repair, genomic stability, and cellular senescence, however, the role of SIRT6 in oxidative stress has not been well clarified. According to recent studies, SIRT6 is believed to protect cells against oxidative stress. Pan et al. (125) found that SIRT6 serves as an NRF2 coactivator by interacting with NRF2 and RNA polymerase II to transactivate NRF2-regulated antioxidant genes, including HO-1. SIRT6 activates AMPK-FoxO3a axis to initiate expression of MnSOD and catalase and protects cardiomyocytes against ischemia/reperfusion-induced injury (126).

6在 DNA 修复、基因组稳定性和细胞衰老中起着重要作用,然而,SIRT6在氧化应激中的作用还没有得到很好的阐明。根据最近的研究,SIRT6被认为可以保护细胞免受氧化应激的侵害。等人(125)发现 SIRT6作为 NRF2辅激活剂,与 NRF2和 RNA聚合酶Ⅱ相互作用,转录 NRF2调节的抗氧化基因,包括 HO-1。SIRT6激活 AMPK-FoxO3a 轴,启动 MnSOD 和过氧化氢酶的表达,保护心肌细胞免受缺血/再灌注损伤(126)。

SIRT7

Sirt7 deficiency in mice induces multisystemic mitochondrial dysfunction (127). SIRT7 deacetylates GABPβ1, a master regulator of nuclear-encoded mitochondrial genes, enables it to form the transcriptionally active GABPa/GABPβ heterotetramer, and promotes mitochondria function (127). Additionally, the mitochondrial unfolded protein response [UPR(mt)] is mediated by the interplay of SIRT7 and NRF1 and is coupled to cellular energy metabolism and proliferation (128).

Sirt7缺乏导致小鼠多系统线粒体功能障碍。SIRT7去乙酰化 gabp1,使其形成转录活性的 gabpa/gabp 异质四聚体,促进线粒体功能(127)。此外,线粒体未折叠蛋白反应受 SIRT7和 NRF1的相互作用调节,并与细胞能量代谢和增殖相耦合。

Sirtuins in Insulin Signaling Pathways

去乙酰化酶在胰岛素信号通路中的作用

Insulin Secretion

胰岛素分泌

Under the condition of insulin resistance, normal pancreatic β cells increase the production of insulin to maintain blood glucose levels. However, this compensatory response fails, and relative insulin insufficiency develops. Then, glucose tolerance is impaired, and T2DM eventually occurs. SIRT1, SIRT4, and SIRT6 reportedly regulate pancreatic β cell function (Figure 1) (24129130). According to accumulating evidence, SIRT1 and SIRT6 repress pancreatic β cell dysfunction, attenuating the development of T2DM. β cell-specific SIRT1 transgenic mice exhibit enhanced insulin secretion and improved glucose tolerance to high glucose stimulation (131). Mechanistically, through repressing UCP2 expression, SIRT1 enhances ATP production in pancreatic β cells, to shut down the potassium channel, resulting in the influx of calcium and finally the secretion of insulin (131132). SIRT1 can induce NeuroD and MafA expression via deacetylating and activating FoxO1, which protects pancreatic β cells against oxidative damage and preserves pancreatic β cells function (133). In contrast to SIRT1 and SIRT6, SIRT4 functions as a negative regulator of insulin secretion in β cells. Glutamate dehydrogenase (GDH) promotes the metabolism of glutamate and glutamine, generating ATP to further promote insulin secretion. In pancreatic β cells, SIRT4 represses the activity of GDH by ADP-ribosylation, thereby downregulating insulin secretion in response to amino acids under calorie-sufficient conditions (20). SIRT4 also controls leucine oxidation to regulate insulin secretion (134). Given that SIRT3 deacetylases GDH and increases its activity in hepatocytes (135), SIRT3 may function in β cell mitochondria to promote insulin secretion. Recent studies have provided evidence to support this notion. Caton et al. observed that SIRT3 expression markedly decreases in islets isolated from T2DM patients, as well as in mouse islets or INS1 cells (136). Sirt3 knockdown in INS1 cells results in increased production of cellular ROS and IL-1β, increased β cell apoptosis and reduced insulin secretion (136). SIRT3 deficiency predisposes pancreatic β cells to oxidative stress-induced dysfunction and reduces glucose-induced insulin secretion (137). By contrast, SIRT3 overexpression inhibits ER stress and attenuates palmitate-induced pancreatic β cell dysfunction (138139). Therefore, SIRT3 and SIRT4 play opposing roles in regulating insulin secretion in pancreatic β cells. In addition, insulin secretion impairment is observed in Sirt6 knockout pancreatic β cells, which is mediated by suppression of the FoxO1-Pdx1-Glut2 pathway (140). Sirt6 deletion in pancreatic β cells also reduces ATP production and increases mitochondrial damage which induces cell apoptosis and impairs glucose-stimulated insulin secretion (129141). β cell-specific Sirt6-ko mice are glucose intolerance and are defective in glucose-stimulated insulin secretion, in spite do not show abnormality in endocrine morphology, pancreatic β cell mass or insulin production (130). Sirt6 deficiency also results in aberrant upregulation of thioredoxin-interacting protein (TXNIP) in pancreatic β cells, which inhibits insulin secretion (130).

在胰岛素抵抗的条件下,正常胰腺细胞增加胰岛素的产量,以维持血糖水平。然而,这种代偿反应失败了,并且出现了相对的胰岛素不足。然后,葡萄糖耐量受损,并最终发生 T2DM。SIRT1,SIRT4,和 SIRT6据报道调节胰腺细胞功能(图1)(24,129,130)。根据不断积累的证据,SIRT1和 SIRT6可抑制胰腺细胞功能障碍,减缓 T2DM 的发生。细胞特异性 SIRT1转基因小鼠对高糖刺激具有增强胰岛素分泌和改善葡萄糖耐量的作用(131)。机制上,通过抑制 UCP2的表达,SIRT1增强了胰腺细胞中 ATP 的产生,关闭了钾离子通道,导致钙的流入,最终分泌胰岛素(131,132)。SIRT1通过去乙酰化和激活 FoxO1诱导 NeuroD 和 MafA 的表达,保护胰腺细胞免受氧化损伤,维持胰腺细胞功能(133)。与 SIRT1和 SIRT6相反,SIRT4在细胞中起到胰岛素分泌的负调节作用。谷氨酸脱氢酶促进谷氨酸和谷氨酰胺的代谢,产生 ATP 进一步促进胰岛素的分泌。在胰腺细胞中,SIRT4通过 ADP核糖基化抑制 GDH 的活性,从而在热量充足的条件下下调胰岛素的分泌。SIRT4还控制亮氨酸氧化调节胰岛素分泌(134)。鉴于 SIRT3去乙酰化酶 GDH 增加肝细胞的活性(135) ,SIRT3可能在细胞线粒体中发挥促进胰岛素分泌的作用。最近的研究提供了支持这一观点的证据。Caton 等人观察到 SIRT3在 T2DM 患者胰岛中的表达明显下降,在小鼠胰岛或 INS1细胞中也是如此(136)。Sirt3基因敲除 INS1细胞后,细胞内 ROS 和 il-1的产生增加,细胞凋亡增加,胰岛素分泌减少(136)。SIRT3缺乏使胰腺细胞易于发生氧化应激引起的功能障碍,并减少葡萄糖引起的胰岛素分泌(137)。相比之下,SIRT3过度表达抑制内质网应激和减轻软脂酸盐诱导的胰腺细胞功能障碍(138,139)。因此,SIRT3和 SIRT4在胰腺细胞胰岛素分泌调节中起着相反的作用。此外,在 Sirt6基因敲除的胰腺细胞中观察到胰岛素分泌障碍,这是通过抑制 FoxO1-Pdx1-Glut2途径(140)来实现的。胰腺细胞 Sirt6缺失也会减少 ATP 的产生,增加线粒体损伤,从而诱导细胞凋亡和损害葡萄糖刺激的胰岛素分泌(129,141)。细胞特异性 Sirt6-ko 小鼠是葡萄糖耐受不良,在葡萄糖刺激的胰岛素分泌方面有缺陷,尽管在内分泌形态、胰腺细胞数量或胰岛素产生方面没有表现出异常(130)。Sirt6缺乏还导致胰腺细胞硫氧还蛋白相互作用蛋白(TXNIP)异常上调,从而抑制胰岛素分泌(130)。FIGURE 1 图1

Figure 1. Sirtuins regulates insulin secretion of pancreatic beta cells. In the nucleus, SIRT1 induces insulin secretion through the reduction of UCP2 expression and the enhancement of depolarization in pancreatic β cells, while SIRT6 deacetylates FOXO1 and promotes the expression of GLUT2, which facilitates glucose uptake and insulin secretion. In the mitochondria, SIRT4 promotes the ADP-ribosylation and inactivation of GDH, leading the repression of ATP generation and inhibition of insulin secretion. UCP2, uncoupling protein 2; Glu, glutamate; GDH, glutamate dehydrogenase; GLUT2, glucose transporter 2; α-KG, alpha-ketoglutarate.

图1。去乙酰化酶调节胰岛 β 细胞的胰岛素分泌。在细胞核内,SIRT1通过减少 UCP2的表达和加强胰腺细胞的去极化来诱导胰岛素分泌,而 SIRT6去乙酰化 FOXO1和促进 GLUT2的表达,促进葡萄糖摄取和胰岛素分泌。在线粒体中,SIRT4促进谷氨酸脱氢酶的 ADP核糖基化和失活,导致 ATP 生成的抑制和胰岛素分泌的抑制。2,解偶联蛋白2; Glu,谷氨酸; GDH,谷氨酸脱氢酶; GLUT2,葡萄糖转运蛋白2;-kg,α- 酮戊二酸。

Insulin Signaling Pathway

胰岛素信号通路

Insulin resistance, the inability of cells to efficiently respond to a normal dose of insulin, is caused by impaired insulin signaling and postreceptor intracellular defects (4). Insulin binding to its receptor results in IR phosphorylating itself and several intracellular substrates. The phosphorylated substrates interact with intracellular effectors, leading to the activation of the PI3K-Akt pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which controls cell growth and differentiation (4142). Impaired Akt activation is a key factor in metabolic disorders involving insulin resistance. Accumulating evidence suggests that Sirtuins participate in insulin signaling in target cells (Figure 2).

胰岛素抵抗,即细胞无法对正常剂量的胰岛素作出有效的反应,是由胰岛素信号受损和受体后细胞内缺陷引起的(4)。胰岛素与其受体的结合导致胰岛素受体本身磷酸化和一些细胞内底物。磷酸化底物与细胞内效应物相互作用,导致胰岛素代谢活动的 PI3K-Akt 通路和控制细胞生长和分化的 Ras-MAPK 通路(4,142)被激活。Akt 激活受损是涉及胰岛素抵抗的代谢紊乱的一个关键因素。越来越多的证据表明 Sirtuins 参与了靶细胞中的胰岛素信号传导(图2)。FIGURE 2 图2

Figure 2. Sirtuins regulates insulin signaling pathways. In nutrient enough conditions, insulin and insulin-like growth factors activate the IRS-PI3K-AKT signaling and downstream FOXO and mTOR signaling to regulate multiple aspects of metabolism, survival, mitochondrial homeostasis, nuclear transcriptional events, and other cellular behaviors. The insulin receptor activation is inhibited by PTPN1, which is repressed by SIRT1. SIRT1 also deacetylates IRS2 and represses IRS1 phosphorylation and PI3K-AKT activation. SIRT1 and SIRT2 also deacetylate AKT to activate its activation directly, while SIRT7 indirectly inhibits AKT activation by deacetylating FKBP51. Under energetic stress or caloric restriction, multiple members of the Sirtuins family are activated. SIRT1, SIRT2, SIRT3, and SIRT6 can directly deacetylate FOXOs (FOXO1 and FOXO3a), while SIRT1 and SIRT2 activate the LKB1-AMPK signaling to activate FOXO and inhibit mTOR signaling. IGF, insulin-like growth factor; IRS, insulin receptor substrate; PTPN1, tyrosine-protein phosphatase non-receptor type 1; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; mTOR, mammalian target of rapamycin; AMPK, AMP-activated protein kinase; LKB1, liver kinase B1; FKBP51, FK506-binding protein 51; GSK3β, glycogen synthase kinase-3 beta.

图2。去乙酰化酶调节胰岛素信号通路。在足够的营养条件下,胰岛素和胰岛素样生长因子激活 IRS-PI3K-AKT 信号和下游 FOXO 和 mTOR 信号,调节代谢、生存、线粒体稳态、核转录事件和其他细胞行为的多个方面。胰岛素受体的激活受到 PTPN1的抑制,而这种抑制被 SIRT1所抑制。SIRT1还使 IRS2去乙酰化,抑制 IRS1磷酸化和 PI3K-AKT 活化。SIRT1和 SIRT2也能直接激活 AKT,而 SIRT7通过去乙酰化 FKBP51间接抑制 AKT 的激活。在能量压力或热量限制下,Sirtuins 家族的多个成员被激活。SIRT1、 SIRT2、 SIRT3和 SIRT6可直接脱乙酰化 FOXOs (FOXO1和 FOXO3a) ,而 SIRT1和 SIRT2激活 LKB1-AMPK 信号通路激活 FOXO 和抑制 mTOR 信号通路。胰岛素样生长因子; 胰岛素样生长因子; IRS,胰岛素受体底物; PTPN1,酪氨酸蛋白磷酸酶非受体型1; PI3K,磷脂酰肌醇 -4,5-二磷酸3- 激酶; mTOR,雷帕霉素靶蛋白; AMPK,AMP活化蛋白激酶; LKB1,肝激酶 B1; FKBP51,fk506-结合蛋白51; gsk3,糖原合成酶 -3 β。

SIRT1 positively regulates insulin signaling and Akt activation at multiple levels. SIRT1 represses transcription of PTPN1, a negative regulator of the insulin signal transduction cascade, at the chromatin level and improves insulin sensitivity (3). Knockdown of Sirt1 in 3T3-L1 adipocytes increases phosphorylation of JNK, as well as serine phosphorylation of insulin receptor substrate 1 (IRS-1), which leads to decrease tyrosine phosphorylation of IRS-1, and then inhibit phosphorylation of Akt (39). Inhibition of SIRT1 activity reduces insulin-induced IRS-2 deacetylation, which prevents insulin-induced IRS-2 tyrosine phosphorylation (143). SIRT1 mediates deacetylation of Akt regulates binding of Akt to phosphatidylinositol 3,4,5-trisphosphate (PIP3) which is necessary for Akt membrane localization and activation (144).

SIRT1在多个水平上正向调节胰岛素信号转导和 Akt 激活。1在染色质水平上抑制 PTPN1的转录,并提高胰岛素敏感性(3)。 PTPN1是胰岛素信号转导级联的负调节因子。敲除3T3-L1脂肪细胞中的 Sirt1可以增加 JNK 的磷酸化程度,也可以增加胰岛素受体底物1(IRS-1)丝氨酸的磷酸化程度,从而降低 IRS-1酪氨酸磷酸化程度,进而抑制 Akt (39)的磷酸化程度。抑制 SIRT1活性降低胰岛素诱导的 IRS-2脱乙酰化,从而阻止胰岛素诱导的 IRS-2酪氨酸磷酸化(143)。SIRT1介导 Akt 的去乙酰化调节 Akt 与3,4,5-三磷酸磷脂酰肌醇(PIP3)的结合,这是 Akt 膜定位和激活所必需的。

SIRT2 can directly regulate the insulin signaling pathway, but its role is controversial. SIRT2 can deacetylate and activate Akt through the Akt/glycogen synthase kinase-3β (GSK3β)/β-catenin signaling pathway, finally resulting in aberrant proliferation and survival of myeloid leukemia cells and epithelial-mesenchymal transition of HCC (145146). Interestingly, Ramakrishnan and colleagues showed that SIRT2 is a novel Akt interactor and is required for optimal Akt activation under normal conditions (147). Pharmacological or genetic inhibition of SIRT2 decreases Akt activation in 3T3-L1 preadipocytes and HeLa cells, whereas SIRT2 overexpression enhances the activation of Akt and its downstream targets, such as GSK3 and p70-S6-kinase (147). Insulin-induced Akt activation requires Akt binding to inositol 1,4,5-trisphosphate, which leads to Akt conformational changes and facilitates its phosphorylation by PDK1 and mTORC1 (147). Acetylation at Lys20 blocks Akt activation by restricting the binding of Akt to inositol 1,4,5-trisphosphate (144). However, the authors were unable to detect Akt acetylation in the experiment, and they could not determine whether the effects of SIRT2 on Akt are dependent on changing the acetylation level of Akt (147). However, the opposite results have also been reported. Arora et al. reported that SIRT2 is upregulated in insulin-resistant skeletal muscle cells, and inhibition of SIRT2 by pharmacological or genetic means improves phosphorylation of Akt and GSK3β and increases insulin-stimulated glucose uptake (148). Similarly, in insulin-resistant neuro-2a cells, inhibition of SIRT2 by pharmacological or genetic means also enhances the activity of Akt and increases insulin-stimulated glucose uptake (149). Therefore, SIRT2 may regulate Akt in both direct (activity-dependent) and indirect (activity-independent) manners, which may largely rely on the metabolic status of the cells. SIRT2 can deacetylate and regulate the function of FOxO transcription factors, which are direct Akt targets (98150). Interestingly, the Akt-independent pathway also contributes to the function of SIRT2 in the regulation of insulin sensitivity. TUG acetylation modulates its interaction with Golgi matrix proteins and enhances its function to trap GLUT4 storage vesicles in intracellular (151). Insulin mobilizes the exocytic translocation of GLUT4 glucose transporters by triggering TUG proteolysis to accelerate glucose uptake in fat and muscle. SIRT2-mediated TUG deacetylation controls insulin sensitivity in vivo and in vitro (151).

SIRT2可直接调节胰岛素信号通路,但其作用尚存争议。SIRT2可通过 Akt/糖原合成酶激酶 -3(gsk3)/-catenin 信号通路脱乙酰化和激活 Akt,最终导致髓系白血病细胞的异常增殖和存活以及 HCC 的上皮-间充质转化(145,146)。有趣的是,Ramakrishnan 和他的同事证明了 SIRT2是一种新的 Akt 互作者,在正常条件下(147)是最佳 Akt 激活所必需的。SIRT2抑制3T3-L1前脂肪细胞和 HeLa 细胞 Akt 激活,而 SIRT2过表达增强 Akt 及其下游靶标 GSK3和 p70-S6-kinase (147)的激活。胰岛素诱导的 Akt 激活需要 Akt 与肌醇1,4,5- 三磷酸结合,这导致 Akt 构象改变,并促进其磷酸化,通过 PDK1和 mTORC1(147)。Lys20的乙酰化通过限制 Akt 与肌醇1,4,5- 三磷酸(144)的结合阻止 Akt 的活化。但作者在实验中未能检测到 Akt 的乙酰化水平,也未能确定 SIRT2对 Akt 的影响是否与 Akt (147)乙酰化水平的改变有关。然而,相反的结果也有报道。Arora 等人报告说,SIRT2在胰岛素抵抗的骨骼肌细胞中上调,通过药理或遗传手段抑制 SIRT2可以改善 Akt 和 gsk3的磷酸化,并增加胰岛素刺激的葡萄糖摄取(148)。同样,在胰岛素抵抗的 neuro-2a 细胞中,通过药理学或遗传学方法抑制 SIRT2也能增强 Akt 的活性并增加胰岛素刺激的葡萄糖摄取(149)。因此,SIRT2可以通过直接(依赖活性)和间接(依赖活性)两种方式调节 Akt,这在很大程度上取决于细胞的代谢状态。SIRT2可以去乙酰化和调节 FOxO 转录因子的功能,这些转录因子是 Akt 的直接靶标(98,150)。有趣的是,与 akt 无关的通路也参与了 SIRT2在调节胰岛素敏感性中的作用。TUG 乙酰化调节其与高尔基体蛋白的相互作用,增强其在细胞内捕获 GLUT4储存囊泡的功能。胰岛素通过触发 TUG 蛋白水解动员 GLUT4葡萄糖转运体的外分泌,加速脂肪和肌肉中的葡萄糖摄取。Sirt2介导的 TUG 脱乙酰基在体内和体外控制胰岛素敏感性(151)。

The role of SIRT6 in the insulin signaling pathway is controversial. Sirt6-deficient mice die about 4 weeks of age, exhibiting severe metabolic defects, including low insulin and hypoglycemia (15). Xiao et al. found that Sirt6 deficiency increases Akt phosphorylation through modulating insulin signaling upstream of Akt, including insulin receptor, IRS1, IRS2, and enhances insulin signaling, leading to hypoglycemia (152). On the contrary, Sirt6 transgenic mice show increased insulin sensitivity in skeletal muscle and liver and exhibit enhanced insulin-induced Akt activation in gastrocnemius (153).

SIRT6在胰岛素信号通路中的作用是有争议的。Sirt6基因缺陷小鼠在4周大时死亡,表现出严重的代谢缺陷,包括低胰岛素和低血糖(15)。肖等人发现,Sirt6缺乏通过调节 Akt 上游的胰岛素信号,包括胰岛素受体、 IRS1、 IRS2,增强 Akt 磷酸化,并增强胰岛素信号,导致低血糖。相反,Sirt6转基因小鼠骨骼肌和肝脏胰岛素敏感性增加,腓肠肌胰岛素诱导的 Akt 激活增强(153)。

In addition, SIRT7 can regulate Akt signaling. SIRT7 regulates the acetylation of FKBP51, which then regulates Akt activation. Acetylated FKBP51 enhances Akt activity by blocking its interaction with PHLPP-Akt. SIRT7 deacetylates FKBP51 at two major lysine residues. SIRT7 suppresses Akt activation and modulates cell sensitivity to genotoxic agents (154). The inhibitory effects of SIRT7 on Akt activation were also observed in murine hearts.

此外,SIRT7可以调节 Akt 信号。SIRT7调节 FKBP51的乙酰化,进而调节 Akt 的激活。乙酰化 FKBP51通过阻断其与 phlpp-Akt 的相互作用增强 Akt 活性。SIRT7在两个主要赖氨酸残基上脱乙酰化 FKBP51。SIRT7抑制 Akt 激活并调节细胞对遗传毒性物质的敏感性(154)。在小鼠心脏中也观察到 SIRT7对 Akt 激活的抑制作用。

Sirtuins in Insulin-Sensitive Organs

胰岛素敏感器官中的去乙酰化酶

Adipose tissue, liver, and muscle are the primary insulin-responsive organs. Insulin regulates blood glucose concentrations by suppressing hepatic glucose output and stimulating glucose uptake by muscle and adipose tissue. In addition, insulin promotes energy storage in adipose tissue, liver, and muscle by stimulating lipogenesis, glycogen, and protein synthesis but inhibiting lipolysis, glycogenolysis and protein catabolism (155).

脂肪组织、肝脏和肌肉是主要的胰岛素应答器官。胰岛素通过抑制肝脏葡萄糖输出和刺激肌肉和脂肪组织对葡萄糖的摄取来调节血糖浓度。此外,胰岛素通过刺激脂肪生成、糖原和蛋白质合成促进脂肪组织、肝脏和肌肉中的能量储存,但是抑制脂肪分解、糖原分解和蛋白质分解(155)。

The impaired lipogenic/adipogenic capacity of adipose tissue leads to increased body fat mass and adverse metabolic consequences (4156). Adipose tissue is not only an excessive energy storage pot but also a highly active endocrine organ that secretes proteins, adipokines, cytokines and chemokines to influence insulin sensitivity. Circulating FFAs derived from adipocytes are involved in the accumulation of triglycerides and fatty acid-derived metabolites in muscle and liver, which is a contributing factor to insulin resistance (155). In addition, adipose tissue is an important initiator of the inflammatory response to obesity (28), and FFAs from adipose tissue are important ER stress-triggering factors (28).

脂肪组织的成脂/成脂能力受损导致体脂质量增加和不良代谢后果(4,156)。脂肪组织不仅是一个能量储存罐,而且是一个分泌蛋白质、脂肪因子、细胞因子和趋化因子影响胰岛素敏感性的高度活跃的内分泌器官。来自脂肪细胞的循环脂肪酸参与了甘油三酯和脂肪酸衍生代谢物在肌肉和肝脏的积累,这是一个影响因素的胰岛素抵抗(155)。此外,脂肪组织是肥胖症炎症反应的重要启动者(28) ,来自脂肪组织的游离脂肪酸是重要的 ER 应激触发因子(28)。

The liver, as the central organ responsible for maintaining lipid and glucose hemostasis in the body, plays a crucial role in insulin sensitivity and metabolic diseases. During prolonged fasting or starvation, the liver converts lipids to available energy through fatty acid oxidation and provides glucose to maintain normal blood glucose, initially by glycogenolysis and then by switching to gluconeogenesis (157158). Under energy abundance conditions, the liver promotes glycogenesis and lipogenesis to store energy. Insulin stimulates glycogen accumulation and blocks gluconeogenesis and glycogenolysis in the liver to suppress hepatic glucose output (155158159). In the condition of insulin resistance, suppression of hepatic glucose output is impaired, while increased FFA from adipocytes leads to ectopic lipid accumulation in the liver, which exacerbates insulin resistance (29).

肝脏作为维持体内脂质和葡萄糖凝血的中枢器官,在胰岛素敏感性和代谢性疾病中起着重要作用。在长时间禁食或饥饿状态下,肝脏通过脂肪酸氧化将脂类转化为可利用的能量,并提供葡萄糖以维持正常的血糖,最初是通过糖原分解,然后转变为葡萄糖异生(157,158)。在能量充足的条件下,肝脏促进糖分生成和脂肪生成以储存能量。胰岛素刺激糖原的积累,并阻止糖异生和糖原分解在肝脏中抑制肝葡萄糖输出(155,158,159)。在胰岛素抵抗的情况下,肝脏葡萄糖输出受到抑制,而脂肪细胞游离脂肪酸增加导致肝脏异位脂质堆积,从而加剧胰岛素抵抗(29)。

Skeletal muscle is the major site for insulin-stimulated glucose disposal in vivo as well as the main energy consumer of lipid catabolism that strongly influences whole-body lipid metabolism (155160). The ability to switch between glucose and lipid oxidation is crucial for skeletal muscle to maintain physiological function and metabolic hemostasis (161). Intramuscular fatty acid metabolite accumulation may cause insulin resistance (162).

骨骼肌是体内胰岛素刺激葡萄糖处理的主要部位,也是强烈影响全身脂质代谢的脂质分解代谢的主要能量消耗者(155,160)。在葡萄糖和脂肪氧化之间转换的能力对于骨骼肌维持生理功能和代谢止血是至关重要的(161)。肌内脂肪酸代谢物积累可能导致胰岛素抵抗(162)。

The functions of Sirtuins in regulating glucose and lipid metabolism as well as insulin sensitivity have been widely investigated in adipose tissue, liver and skeletal muscles (Figure 3).

Sirtuins 在调节葡萄糖和脂质代谢以及胰岛素敏感性方面的功能已经在脂肪组织、肝脏和骨骼肌中得到了广泛的研究(图3)。FIGURE 3 图3

Figure 3. Sirtuins regulates metabolism in insulin-target organs. The functions of Sirtuins in the regulation of glucose and fatty acid metabolism in the liver, adipose tissue, and skeletal muscle. The (–) indicates Sirtuin represses the activation/expression of this target, whereas (+) indicates Sirtuin promotes the activation/expression of the target. The green background indicates Sirtuin promotes the biological process whereas the pink background indicates the Sirtuin represses the biological process. PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; TORC2, CREB regulated transcription coactivator 2; PPARα, peroxisome proliferator-activated receptor alpha; SREBP1c, Sterol response element-binding protein 1c; AMPK, AMP-activated protein kinase; HIF1α, hypoxia-inducible factor 1 alpha; PGAM-1, phosphoglycerate mutase 1; CRTC2, CREB regulated transcription coactivator 2; PPARγ, peroxisome proliferator-activated receptor gamma; Prdm16, PR domain containing 16; PEPCK1, phosphoenolpyruvate carboxykinase 1; LCAD, long-chain acyl-CoA dehydrogenase; PDH, pyruvate dehydrogenase; IDH2, isocitrate dehydrogenase; NDUFA9, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9; SDH, succinate dehydrogenase; HK2, hexokinase 2; MCD, malonyl-CoA decarboxylase; ECHA, trifunctional enzyme subunit alpha; HCDH, hydroxyacyl-Coenzyme A dehydrogenase; GAPDH, Glyceraldehyde 3-phosphate dehydrogenase; SREBP-2, sterol regulatory element-binding protein 2; ACC, acetyl-CoA carboxylase; SCD, stearoyl-CoA desaturase; FAS, fatty acid synthase; GK, glucokinase; GCN5, general control non-repressed protein 5; KIF5C, kinesin heavy chain isoform 5C; GABPβ1, GA binding protein β1; DCAF1/DDB1/GUL4B, DDB1-CUL4-associated factor 1 (DCAF1)/damage-specific DNA binding protein 1 (DDB1)/cullin 4B (CUL4B) complex; PGK1, phosphoglycerate kinase 1; G6PC, glucose-6-phosphatase, catalytic subunit; GKRP, glucokinase regulatory protein.

图3。去乙酰化酶调节胰岛素靶器官的代谢。去乙酰化酶在肝脏、脂肪组织和骨骼肌中调节葡萄糖和脂肪酸代谢的功能。(-)表明 Sirtuin 抑制该靶点的激活/表达,而(+)表明 Sirtuin 促进该靶点的激活/表达。绿色背景表明去乙酰化酶促进生物过程,而粉色背景表明去乙酰化酶抑制生物过程。1,过氧化物酶体增殖物活化受体γ 辅激活子1-alpha,TORC2,CREB 调节转录辅激活子2,ppar,过氧化物酶体增殖物活化受体 α;1,缺氧诱导因子1 α; PGAM-1,磷酸甘油酸突变酶1; CRTC2,CREB 调节转录辅激活因子2; ppar,过氧化物酶体增殖物活化受体γ;Prdm16,PR 结构域包含16; PEPCK1,磷酸烯醇丙酮酸羧化激酶1; LCAD,长链酰基辅酶 a 脱氢酶; PDH,丙酮酸脱氢酶; IDH2,异柠檬酸脱氢酶;9,NADH脱氢酶辅酶 a 亚基; SDH,琥珀酸脱氢酶; HK2,己糖激酶2; MCD,丙二酰辅酶A脱羧酶; ECHA,三功能酶 α 亚基; HCDH,羟酰辅酶 a 脱氢酶; GAPDH,甘油醛3-磷酸脱氢酶; SREBP-2,固醇调节元件结合蛋白2;乙酰辅酶A羧化酶; SCD,固醇辅酶A去饱和酶1; FAS,脂肪酸合酶; GK,葡萄糖激酶; GCN5,一般控制非抑制蛋白5; KIF5C,激肽重链5C; gabp 1,GA 结合蛋白1;DCAF1/DDB1/GUL4B,DDB1-cul4相关因子1(DCAF1)/损伤特异性 DNA 结合蛋白1(DDB1)/cullin 4B (CUL4B)复合物; PGK1,磷酸甘油酸激酶1; G6PC,葡萄糖亚单位6- 磷酸酶,催化; GKRP,葡萄糖激酶调节蛋白。

SIRT1 and Insulin-Sensitive Organs

SIRT1与胰岛素敏感器官

SIRT1 Regulates Fatty Acid and Glucose Metabolism in the Liver

SIRT1对肝脏脂肪酸和葡萄糖代谢的调节作用

The role of SIRT1 in regulating hepatic gluconeogenesis is controversial under the condition of calorie restriction. Resveratrol has been shown to improve glucose homeostasis in insulin-resistant mice by reducing hepatic gluconeogenesis and increase insulin sensitivity in adipose tissue, skeletal muscle and liver (163). On the contrary, resveratrol causes nuclear translocation of FoxO1 in hepatocytes viaSIRT1-dependent deacetylation, which leads to activation of gluconeogenesis and increased hepatic glucose output (164). Pyruvate induces SIRT1 protein in the liver during fasting, and once SIRT1 is induced, which can increase gluconeogenic genes expression and promote hepatic glucose output through interacting and deacetylating PGC-1α (165). Conversely, during prolonged fasting, SIRT1 deacetylates CREB regulated transcription coactivator 2 (CRTC2) and promotes its ubiquitin-dependent degradation to inhibit gluconeogenic gene expression, leading to decreased hepatic glucose output (166). On the other hand, upregulation of FOXO1 and PGC-1α activity by SIRT1 leads to activation of gluconeogenic gene expression in hepatic cells and increase hepatic glucose production (157166). In addition, SIRT1 regulates the activity of PGC-1α, and glycolytic enzyme phosphoglycerate mutase-1 (PGAM1), inducing repression of glycolytic genes in response to fasting (165167). These studies suggest an important role of SIRT1 in maintaining energy balance under fasting. Liver-specific Sirt1 ko mice develop hepatic steatosis when underwent fasting and obesity when fed with HFD in insulin-dependent and independent manners (38168). Sirt1 transgenic mice show better glucose tolerance and insulin sensitivity and are almost entirely protected from hepatic steatosis with HFD treatment (37169). On one hand, SIRT1 deacetylates and activates PGC-1α, increasing fatty acid β-oxidation in the liver (38). On the other hand, SIRT1 plays an important role in inhibiting lipogenesis in the liver. For example, resveratrol can increase the levels of sterol regulatory element-binding protein (SREBP), a critical regulator of lipid and sterol homeostasis in eukaryotes, in livers of alcohol-treated mice and alleviate alcoholic fatty liver (170). SRT1720, a SIRT1 activator, ameliorates fatty liver through suppressing the expression of lipogenic enzymes, including SREBP-1c, acetyl-CoA carboxylase, and fatty acid synthase, in obesity and insulin resistant mice (171). SIRT1 can directly deacetylate SREBP, and control SREBP protein stability via SREBP ubiquitination, leading to attenuating SREBP target lipogenic gene expression and inhibiting lipid synthesis and fat storage (172). Otherwise, SIRT1 activation by polyphenols acts as an upstream regulator in the LKB1/AMPK signaling axis, resulting in repression expression of acetyl-CoA carboxylase and fatty acid synthase and reduction of lipid accumulation in hepatocytes (173).

在卡路里限制条件下,SIRT1在调节肝脏糖异生中的作用是有争议的。白藜芦醇通过减少肝糖异生和增加脂肪组织、骨骼肌和肝脏(163)的胰岛素敏感性,改善胰岛素抵抗小鼠的葡萄糖稳态。相反,白藜芦醇通过 sirt1依赖的去乙酰化作用引起肝细胞 FoxO1核转位,从而激活葡萄糖异生和增加肝糖输出(164)。丙酮酸在禁食期间在肝脏中诱导 SIRT1蛋白,一旦诱导 SIRT1,可通过相互作用和去乙酰化 pgc-1(165)增加糖异生基因的表达和促进肝脏葡萄糖输出。相反,在长时间禁食期间,SIRT1去乙酰化 CREB 调节转录辅激活因子2(CRTC2) ,促进其依赖泛素的降解,以抑制糖异生基因的表达,导致肝糖输出量下降(166)。另一方面,SIRT1对 FOXO1和 pgc-1活性的上调导致肝细胞葡萄糖异生基因表达的激活和肝糖产量的增加(157,166)。此外,SIRT1还调节 pgc-1和糖酵解酶磷酸甘油酸变异酶 -1(PGAM1)的活性,诱导糖酵解基因对禁食的抑制(165,167)。这些研究表明 SIRT1在禁食状态下维持能量平衡的重要作用。肝特异性 Sirt1 ko 小鼠在以胰岛素依赖和独立方式喂食 HFD 后,在禁食和肥胖时发生肝脂肪变性(38,168)。Sirt1转基因小鼠表现出更好的葡萄糖耐量和胰岛素敏感性,并且通过 HFD 治疗几乎完全避免了肝脏脂肪变性(37,169)。一方面,SIRT1可以去乙酰化并激活 pgc-1,增加肝脏中的脂肪酸氧化。另一方面,SIRT1在抑制肝脏脂肪生成中起重要作用。例如,白藜芦醇可以提高经过酒精处理的小鼠肝脏中的固醇调节元件结合蛋白(SREBP)的水平,减轻脂肪肝(170)。固醇调节元件结合蛋白是真核生物脂质和固醇稳态的关键调节剂。SRT1720是一种 SIRT1激活剂,通过抑制肥胖和胰岛素抵抗小鼠(171)的 SREBP-1c、乙酰辅酶A羧化酶和脂肪酸合酶等脂肪生成酶的表达,改善脂肪肝。SIRT1能直接脱乙酰基 SREBP,并通过 SREBP 泛素化调控 SREBP 蛋白的稳定性,从而降低 SREBP 靶基因的表达,抑制脂质合成和脂肪储存(172)。另外,多酚激活 SIRT1作为 LKB1/AMPK 信号轴的上游调节因子,导致乙酰辅酶A羧化酶和脂肪酸合酶蛋白的抑制表达和减少肝细胞中的脂质积累。

SIRT1 Regulates Adipocyte Differentiation and Adipogenesis

SIRT1对脂肪细胞分化和脂肪生成的调控

PPARγ and CCAAT/enhancer-binding protein α (C/EBPα) are master regulators of adipogenesis (156174). SIRT1 overexpression inhibits the expression of PPARγ and C/EBPα in 3T3-L1 adipocytes (175). SIRT1 represses PPARγ by docking with its cofactors nuclear receptor co-repressor (NCoR) and silencing mediator of retinoid and thyroid hormone receptors (SMRT) and suppresses adipogenesis (175). In differentiated fat cells, upregulation of SIRT1 by resveratrol triggers lipolysis and loss of fat, but SIRT1 inhibitor nicotinamide reduces the release of free fatty acid (175).

Ppar 和 ccaat/增强子结合蛋白(c/ebp)是脂肪形成的主要调节因子(156,174)。SIRT1过表达抑制3T3-L1脂肪细胞 ppar 和 c/ebp 的表达。SIRT1通过与其辅助因子核受体共抑制因子(NCoR)和沉默调节因子视黄酸和甲状腺激素受体(srt)对接抑制 ppar,并抑制脂肪生成(175)。在分化的脂肪细胞中,白藜芦醇上调 SIRT1,引发脂肪分解和脂肪损失,但 SIRT1抑制剂烟酰胺减少游离脂肪酸(175)的释放。

SIRT1 Regulates Lipid Metabolism in Skeletal Muscle

1调节骨骼肌中的脂质代谢

There is a strong correlation between the presence of intramyocellular lipid in skeletal muscle and liver and progression of T2DM (176177). Fasting induces PGC-1α deacetylation by SIRT1 in skeletal muscle, and that is required for activation of mitochondrial fatty acid oxidation genes (178). SIRT1 overexpression protects C2C12 myotubes against fatty acid-induced insulin resistance through transcriptional repression of PTP1B (3). In skeletal muscle, SIRT1 acts downstream of AMPK signaling, deacetylates and modulates the activity of PGC-1α, FOXO1, and FOXO3a to inhibit lipogenesis and promote energy consumption (179). SIRT1 overexpression or resveratrol treatment increases insulin-induced Akt phosphorylation and activation via interacting with the PI3K adapter subunit p85 (180). These studies suggest SIRT1 plays a positive role in ameliorating insulin sensitivity in skeletal muscle. However, several studies have demonstrated that skeletal muscle-specific overexpression of SIRT1 does not enhance whole-body energy expenditure or skeletal muscle insulin sensitivity under normal or overfeeding conditions (181182). These controversial results suggest SIRT1 in other metabolic tissues, such as adipose tissue, liver or intestinal tissue, may play a role in the metabolic benefits of SIRT1 activation (183). Notably, high-intensity interval training increases SIRT1 activity in human skeletal muscle and mice with muscle-specific inactivation of the SIRT1 deacetylase domain displayed reduced myofiber size, impaired muscle regeneration, and derepression of muscle developmental genes (184185). Therefore, SIRT1-mediated metabolic balance is important for skeletal muscle homeostasis and regeneration.

骨骼肌和肝脏内肌细胞内脂质的存在与 T2DM 的进展密切相关(176,177)。禁食诱导骨骼肌中的 pgc-1脱乙酰基,这是线粒体脂肪酸氧化基因(178)激活所必需的。SIRT1过表达保护 C2C12肌管对脂肪酸诱导的胰岛素抵抗通过转录抑制 PTP1B (3)。在骨骼肌中,SIRT1作用于 AMPK 信号的下游,去乙酰化并调节 pgc-1、 FOXO1和 FOXO3a 的活性,以抑制脂肪生成并促进能量消耗(179)。SIRT1过表达或白藜芦醇治疗增加胰岛素诱导的 Akt 磷酸化和活化通过与 PI3K 适配器亚基 p85(180)相互作用。这些研究表明,SIRT1在改善骨骼肌胰岛素敏感性方面具有积极作用。然而,一些研究表明,骨骼肌特异性过度表达 SIRT1并不增加全身能量消耗或骨骼肌胰岛素敏感性在正常或过度摄食条件下(181,182)。这些有争议的结果表明,SIRT1在其他代谢组织,如脂肪组织,肝脏或肠组织,可能发挥作用的代谢利益的 SIRT1活化(183)。值得注意的是,高强度间歇训练增加了人类骨骼肌中 SIRT1的活性,并且在肌肉特异性失活 SIRT1去乙酰化酶结构域的小鼠表现出减小的肌纤维大小,受损的肌肉再生和肌肉发育基因的去抑制。因此,sirt1介导的代谢平衡对骨骼肌稳态和再生具有重要意义。

SIRT2 and Insulin-Sensitive Organs

SIRT2与胰岛素敏感器官

SIRT2 Regulates Adipocyte Differentiation and Adipogenesis

SIRT2调节脂肪细胞分化和脂肪生成

SIRT2 is widely distributed and has been detected in a wide range of metabolic tissues, including the brain, muscle, liver, pancreas and adipose tissue. SIRT2 expression is regulated by metabolic status. For instance, the expression of SIRT2 is elevated in the white adipose tissue (WAT) of cr mice (98). SIRT2 gene expression increased in the peripheral blood mononuclear cells of obese subjects following an 8-week hypocaloric diet (186). By contrast, SIRT2 protein expression in visceral WAT from human obese subjects and a mouse model of diet-induced obesity is downregulated compared with that in WAT from lean controls (187). SIRT2 gene expression is significantly lower in peripheral blood mononuclear cells of obese children with insulin resistance than in those without insulin resistance (188). A growing body of literature has indicated that SIRT2 is involved in regulating various metabolic processes, including adipocyte differentiation, hepatic gluconeogenesis, and insulin action. SIRT2 mRNA is more abundant than other Sirtuins in adipose tissue in vivo and preadipocytes in culture (150), implicating the possible important role of SIRT2 in adipose tissue. FOXO1 acts as an adipogenesis inhibitor (189). In adipose tissue, FOXO1 can interact with PPARγ and negatively regulate its transcriptional activity (190) or bind to the PPARγ promoter region and suppress its expression (191). In mouse 3T3-L1 preadipocytes, SIRT2 interacts with and deacetylates FOXO1, which antagonizes FOXO1 phosphorylation and promotes nuclear retention of FOXO1, leading to repression of the expression of PPARγ and C/EBPα as well as genes marking terminal adipocyte differentiation, such as Glut4, aP2, and fatty acid synthase (150). SIRT2 also suppresses adipogenesis by deacetylating FOXO1 to promote the binding of FOXO1 to PPARγ and subsequent repression of PPARγ transcriptional activity (192). Increased de novo lipogenesis is an important contributor to increased adipose mass (193). ATP-citrate lyase (ACLY) is the building block for de novo lipid synthesis, which converts glucose-derived citrate into acetyl-CoA (194). ACLY is acetylated on multiple lysine residues in response to high glucose and promotes lipogenesis, while SIRT2 deacetylates and destabilizes ACLY, leading to reduced lipogenesis (195). Transcriptional regulators such as PPARs and the coactivator PGC-1α play key roles in the process of fatty acid β-oxidation, which determines whole-body energy expenditure (196). Through transcriptional repression of SIRT2, hypoxia-inducible factor 1α (HIF1α) decreases deacetylation of PGC-1α and further diminishes fatty acid β-oxidation in WAT. Adipocyte-specific HIF1α inactivation leads to increased expression of SIRT2 and attenuates dietary-driven obesity in mice (187). These studies suggest that SIRT2 contributes to the control of adipose tissue mass by inhibiting adipogenesis and lipogenesis but promoting fatty acid β-oxidation.

SIRT2分布广泛,广泛存在于大脑、肌肉、肝脏、胰腺和脂肪组织等代谢组织中。SIRT2的表达受代谢状态调节。例如,SIRT2的表达在 cr 鼠(98)的白色脂肪组织(WAT)中升高。在8周低热量饮食(186)后,肥胖者外周血单个核细胞 SIRT2基因表达增加。相比之下,来自人类肥胖受试者和饮食诱导肥胖小鼠模型的内脏 WAT 中 SIRT2蛋白的表达与来自瘦对照组的 WAT 蛋白的表达(187)相比下降。肥胖儿童胰岛素抵抗组外周血单个核细胞 SIRT2基因表达明显低于非胰岛素抵抗组(188)。越来越多的文献表明,SIRT2参与调节多种代谢过程,包括脂肪细胞分化、肝糖异生和胰岛素作用。SIRT2 mRNA 在体内脂肪组织和体外培养前脂肪细胞中的含量较其他 Sirtuins 丰富(150) ,提示 SIRT2在脂肪组织中可能起重要作用。FOXO1作为脂肪生成抑制剂(189)。在脂肪组织中,FOXO1可与 ppar 相互作用,负性调节其转录活性(190) ,或与 ppar 启动子区结合,抑制其表达(191)。在小鼠3T3-L1前脂肪细胞中,SIRT2与 FOXO1相互作用并去乙酰化,这种作用可拮抗 FOXO1磷酸化并促进 FOXO1核保留,导致 ppar 和 c/ebp 以及终端脂肪细胞分化基因如 Glut4、 aP2和脂肪酸合酶蛋白(150)的表达受抑。SIRT2还通过去乙酰化 FOXO1抑制脂肪生成,促进 FOXO1与 ppar 的结合,并抑制 ppar 的转录活性(192)。新生脂肪形成的增加是增加脂肪质量的重要因素(193)。柠檬酸酯裂解酶(ACLY)是从头合成脂质的基石,它将葡萄糖衍生的柠檬酸转化为乙酰辅酶 a (194)。ACLY 在多个赖氨酸残基上被乙酰化以应对高糖并促进脂肪生成,而 SIRT2去乙酰化并使 ACLY 不稳定,导致脂肪生成减少(195)。转录调节因子如 PPARs 和辅激活因子 pgc-1在脂肪酸氧化过程中起关键作用,决定全身能量消耗(196)。缺氧诱导因子1(hif1)通过 SIRT2的转录阻遏作用降低 pgc-1的脱乙酰度,进一步减少 WAT 中的脂肪酸氧化。脂肪细胞特异性的 hif1失活导致 SIRT2的表达增加,并减轻饮食导致的小鼠肥胖(187)。这些研究表明,SIRT2有助于控制脂肪组织的质量,抑制脂肪生成和脂肪形成,但促进脂肪酸氧化。

SIRT2 Participates in Gluconeogenesis in the Liver

SIRT2参与 Gluconeogenesis 肝脏病变的研究

SIRT2 deacetylates and subsequently increases the stability of PEPCK1, the gluconeogenic rate-limiting enzyme under conditions of glucose deprivation, leading to increased gluconeogenesis (197198). FOXO1 and PGC-1α reportedly activate the process of gluconeogenesis in the liver by increasing the transcription of gluconeogenic enzyme genes and are considered negative regulators of insulin sensitivity in the liver (199201). Insulin suppresses gluconeogenesis by regulating the FOXO1-PGC-1α interaction (199). SIRT2 deacetylates and activates FOXO1/PGC-1α in adipocytes (150187192), which implies that SIRT2 may enhance gluconeogenesis through the FOXO1-PGC-1α pathway. However, whether the role of SIRT2 in gluconeogenesis depends on different nutrient conditions must be elucidated. In addition, the roles of SIRT2 in metabolic diseases are largely unknown.

SIRT2脱乙酰基,随后增加了 PEPCK1的稳定性,这是一种在葡萄糖剥夺条件下的糖异生速率限制酶,导致了增加的糖异生(197,198)。FOXO1和 pgc-1据报道通过增加糖异生酶基因的转录激活肝脏的糖异生过程,被认为是肝脏胰岛素敏感性的负调节因子(199-201)。胰岛素通过调节 foxo1-pgc-1相互作用抑制糖异生(199)。SIRT2去乙酰化并激活脂肪细胞 FOXO1/PGC-1,提示 SIRT2可能通过 foxo1-pgc-1途径促进糖异生。然而,SIRT2在糖异生中的作用是否取决于不同的营养条件还有待进一步阐明。此外,SIRT2在代谢性疾病中的作用目前尚不清楚。

SIRT3

Human SIRT3 is expressed in a variety of metabolically active tissues, including muscle, liver, kidney, heart, brain, and BAT (202204). The expression of SIRT3 in the liver and adipose tissue of mice increases during cr (205208). A single nucleotide polymorphism in the human SIRT3 gene has been correlated with the reduced enzymatic efficiency of SIRT3 and the development of metabolic syndrome (209). Compared with WT mice, Sirt3-KO mice fed an HFD show accelerated obesity, insulin resistance, hyperlipidemia, and hepatic steatosis (209).

人类 SIRT3在各种代谢活跃的组织中表达,包括肌肉、肝脏、肾脏、心脏、大脑和 BAT (202-204)。SIRT3在小鼠肝脏和脂肪组织中的表达在 cr (205ー208)期间增加。人类 SIRT3基因中的单核苷酸多态性与 SIRT3的酶效率降低和代谢症候群的发育有关。与 WT 小鼠相比,喂食 HFD 的 Sirt3-KO 小鼠显示肥胖、胰岛素抵抗、高脂血症和肝脏脂肪变性(209)。

SIRT3 Participates in WAT/BAT Metabolism and Thermogenesis

SIRT3参与 WAT/BAT 的代谢和产热

High levels of SIRT3 occur in the BAT. Cold exposure upregulates SIRT3 expression in the BAT. Increasing the expression of PGC-1α and uncoupling protein 1 (UCP1) by sustained expression of SIRT3 in brown adipocytes leads to increased thermogenesis (7206). Fatty acid β-oxidation in the BAT of Sirt3-KO mice is significantly reduced (210). Although SIRT3 maintains a low level in WAT (206), several studies refer to the role of SIRT3 in regulating WAT lipid metabolism. cr activates SIRT3 expression in both white and brown adipose tissue; SIRT3 expression decreases in the BAT of several lines of genetically obese mice (206). In a human study, SIRT3 gene expression was decreased in VAT from morbid subjects (211) and WAT from children with obesity (212). Although the role of SIRT3 in WAT lipid metabolism is intricate and unclear, these studies suggest that SIRT3 may play a protective role in obesity.

在最佳可得技术中出现高水平的 SIRT3。冷暴露上调 BAT 中 SIRT3的表达。在棕色脂肪细胞中,SIRT3的持续表达增加了 pgc-1和 UCP1的表达,从而导致了生热作用的增强(7,206)。Sirt3-KO 小鼠的 BAT 脂肪酸氧化明显降低(210)。虽然 SIRT3在 WAT (206)中维持低水平,但一些研究提到 SIRT3在规范 WAT 脂质代谢中的作用。Cr 激活了白细胞和褐色脂肪组织细胞中 SIRT3的表达,几系遗传性肥胖小鼠(206)的 BAT 中 SIRT3的表达下降。在一项人体研究中,来自病态受试者(211例)和肥胖儿童(212例)的 SIRT3基因表达在 VAT 中降低。虽然 SIRT3在小儿麻痹症脂质代谢中的作用是错综复杂和不清楚的,但这些研究表明,SIRT3可能在肥胖中起到保护作用。

SIRT3 Regulates Fatty Acid Oxidation in the Liver

SIRT3对肝脏脂肪酸氧化的调节作用

Sirt3-deficient mice show higher levels of fatty acid β-oxidation intermediate products and triglycerides in the liver during fasting and develop hepatic steatosis (210). Metabolomic analyses of fasted Sirt3-deficient mice revealed that SIRT3 is involved in fatty acid β-oxidation and modulates fatty acid β-oxidation at multiple points, such as short-chain L-3-hydroxy acyl-CoA dehydrogenase (SCHAD), very-long-chain acyl-CoA dehydrogenase (VLCAD) and 3-ketoacyl-CoA thiolase, in addition to LCAD (208). LCAD is a key enzyme in mitochondrial fatty acid β-oxidation, and LCAD deficiency causes hepatic steatosis and hepatic insulin resistance (213214). SIRT3 promotes hepatic fatty acid β-oxidation through deacetylation and activation of LCAD (210). However, hepatocyte-specific Sirt3-KO mice do not show any obvious metabolic phenotype under either chow or HFD conditions, despite a marked global hyperacetylation of mitochondrial proteins (215). These conflicting findings from global Sirt3-KO mice and tissue-specific KO mice suggest that the roles of SIRT3 in other cell types may be important for SIRT3-mediated metabolic effects in the liver.

Sirt3缺陷小鼠在禁食期间肝脏脂肪酸氧化中间产物和甘油三酯水平较高,并发展为肝脏脂肪变性(210)。对 SIRT3缺陷小鼠的代谢组学分析表明,SIRT3参与脂肪酸氧化,并在多个位点调节脂肪酸氧化,如短链 l-3- 羟基酰基辅酶 a 脱氢酶(SCHAD)、超长链酰基辅酶 a 脱氢酶(VLCAD)和3- 酮酰基辅酶 a 硫醇酶(LCAD)。LCAD 是线粒体脂肪酸氧化的关键酶,LCAD 缺乏导致肝脏脂肪变性和肝脏胰岛素抵抗(213,214)。SIRT3通过去乙酰化和激活 LCAD (210)促进肝脏脂肪酸氧化。然而,肝细胞特异性 Sirt3-KO 小鼠在饲料条件或 HFD 条件下,尽管线粒体蛋白质有明显的全局高乙酰化(215) ,但没有显示任何明显的代谢表型。这些来自全球 SIRT3-KO 小鼠和组织特异性 KO 小鼠的相互矛盾的发现表明,SIRT3在其他细胞类型中的作用可能对 SIRT3介导的肝脏代谢效应有重要意义。

SIRT3 Regulates Glucose Metabolism in Skeletal Muscle

SIRT3对骨骼肌葡萄糖代谢的调节作用

SIRT3 expression decreases in the skeletal muscle of diabetic and HFD-fed mice (36216). CR and exercise upregulate SIRT3 expression in mouse skeletal muscle (162). These findings suggest that SIRT3 is involved in skeletal muscle metabolism. Although muscle-specific Sirt3 KO in mice shows no obvious effects on global metabolic hemostasis under normal conditions (215), striking results have been shown in global Sirt3-KO mice. Global Sirt3-KO mice exhibit decreased oxygen consumption and enhanced oxidative stress in skeletal muscle that leads to impaired insulin signaling (36). The deletion of Sirt3 in vivo and in vitro induces hyperacetylation of the pyruvate dehydrogenase (PDH) E1α subunit and leads to decreased PDH enzymatic activity (161). Inhibition of PDH activity reduces glucose oxidation and results in a switch to fatty acid β-oxidation, thus leading to a loss of skeletal muscle metabolic flexibility (161). In addition, HFD-fed Sirt3-KO mice exhibit increased insulin resistance due to defects in skeletal muscle glucose uptake (217). These studies suggest that SIRT3 may protect insulin sensitivity in skeletal muscle.

SIRT3在糖尿病和 HFD-fed 小鼠骨骼肌中的表达减少(36,216)。CR 与运动上调小鼠骨骼肌 SIRT3的表达(162)。这些发现表明 SIRT3参与了骨骼肌的新陈代谢。虽然在正常情况下,肌肉特异性 Sirt3 KO 对全身代谢止血没有明显的影响(215) ,但是在全身 Sirt3-KO 小鼠中已经有了惊人的结果。全球 Sirt3-KO 小鼠表现出氧消耗减少和骨骼肌氧化应激增强,导致胰岛素信号受损(36)。Sirt3在体内和体外的缺失引起丙酮酸脱氢酶 e1亚基的高乙酰化,导致 PDH 酶活性降低(161)。抑制 PDH 活性降低葡萄糖氧化和结果转向脂肪酸氧化,从而导致失去骨骼肌代谢灵活性(161)。另外,由于缺乏骨骼肌葡萄糖摄取(217) ,HFD-fed Sirt3-KO 小鼠表现出增加的胰岛素抵抗。这些研究表明,SIRT3可以保护骨骼肌的胰岛素敏感性。

SIRT4

SIRT4 Regulates Lipogenesis

SIRT4调控脂质合成

The expression of SIRT4 is upregulated in the liver and adipose tissues in rodents fed an HFD (218219). SIRT4 deacetylates and inhibits malonyl CoA decarboxylase (MCD), an enzyme producing acetyl-CoA from malonyl CoA, consequently repressing fatty acid oxidation but promoting lipogenesis in WAT and skeletal muscle under nutrient abundance conditions. Sirt4-KO mice display increased exercise tolerance and protection against diet-induced obesity (220).

SIRT4的表达上调肝脏和脂肪组织的啮齿类动物饲养的手足口病(218,219)。SIRT4脱乙酰化酶抑制丙二酰辅酶 a 脱羧酶(MCD) ,在营养丰富的条件下抑制脂肪酸的氧化,促进脂肪酸的形成。Sirt4-KO 小鼠显示增加运动耐量和保护对饮食诱导的肥胖(220)。

SIRT4 Regulates Fatty Acid Oxidation

SIRT4对脂肪酸氧化的调节作用

SIRT4 inhibition in mouse primary hepatocytes increases fatty acid oxidation gene expression, leading to increased fat oxidative capacity in liver (118). The same result is obtained in muscle (118). Similarly, primary hepatocytes from Sirt4-KO mice exhibit higher rates of fatty acid oxidation. SIRT4 suppresses PPARα activity and inhibits hepatic fatty acid oxidation by modulating SIRT1 activity (221). Livers from NAFLD patients exhibit increased SIRT4 and lipogenic gene expression (222). These results support the notion that SIRT4 is likely to inhibit fatty acid oxidation and potentiate ectopic lipid storage in liver and skeletal muscle.

SIRT4抑制小鼠原代肝细胞脂肪酸氧化基因表达,导致肝脏脂肪氧化能力增强(118)。在肌肉(118)中也得到同样的结果。同样,Sirt4-KO 小鼠的原代肝细胞表现出较高的脂肪酸氧化率。SIRT4通过调节 SIRT1活性抑制 ppar 活性和抑制肝脏脂肪酸氧化。NAFLD 患者肝脏 SIRT4和脂肪基因表达增加(222)。这些结果支持 SIRT4可能抑制脂肪酸氧化和加强肝脏和骨骼肌异位脂质储存的概念。

SIRT5

SIRT5 in the Regulation of Fatty Acid Metabolism

5在《脂肪酸代谢管理条例》中的应用

SIRT5 is highly expressed in metabolic tissues, including the heart, skeletal muscle, brain, liver, and kidney (121). Using a label-free quantitative proteomic approach, Rardin et al. characterized the lysine succinylome in liver mitochondria and revealed a major role for SIRT5 in regulating many metabolic pathways, including β-oxidation and ketogenesis (223). Park et al. revealed that SIRT5 desuccinylates a set of metabolic enzymes in mitochondria that are involved in amino acid degradation, the TCA cycle and fatty acid metabolism (224). In contrast to the other two mitochondrial Sirtuins, SIRT5 protein levels do not change during CR (121207). However, similar to Sirt3-KO and Sirt4-KO mice, Sirt5-KO mice do not show any overt metabolic abnormalities under either normal chow or HFD conditions (225). Sirt5 deficiency does not protect or sensitize mice to the development of HFD-induced obesity, hypertension, and insulin resistance (225). The results from Sirt5-KO mice suggest that SIRT5 is not dispensable for cellular metabolism, at least under normal conditions. Subsequent studies have shown promising results. In humans, SIRT5 gene expression decreases in the liver of NAFLD patients (222), and the expression of SIRT5 in adipose tissue is positively correlated with insulin sensitivity (226). Using affinity enrichment and label-free quantitative proteomics, Nishida et al. characterized the SIRT5-regulated lysine malonylome (227). Pathway analysis identified gluconeogenesis and glycolysis as the pathways most enriched in SIRT5-regulated malonylated proteins (227). SIRT5 regulates glyceraldehyde phosphate dehydrogenase (GAPDH), a glycolytic enzyme, through demalonylation of lysine 184 (227). According to these results, SIRT5 may play a critical role in regulating glucose and lipid metabolism and preserving insulin sensitivity. Mitochondria-specific Sirtuin knockout mice show no obvious metabolic abnormalities, indicating that mitochondrial Sirtuins serve as nutrient sensors to maintain energy homeostasis.

SIRT5在代谢组织中高度表达,包括心脏、骨骼肌、大脑、肝脏和肾脏(121)。利用无标记的定量蛋白质组学方法,Rardin 等人对肝线粒体中赖氨酸琥珀酰基进行了表征,并揭示了 SIRT5在调节许多代谢途径中的重要作用,包括氧化和酮生成(223)。Park 等人揭示了 SIRT5在线粒体中去琥珀酰基化了一系列代谢酶,这些酶参与了氨基酸的降解,TCA 循环和脂肪酸代谢。与其他两种线粒体 Sirtuins 相比,SIRT5蛋白水平在 CR (121,207)期间没有变化。然而,与 Sirt3-KO 和 Sirt4-KO 小鼠相似,Sirt5-KO 小鼠在正常食物或 HFD 条件下都没有显著的代谢异常(225)。缺乏 Sirt5不能保护或敏感小鼠发展为 hfd 诱导的肥胖、高血压和胰岛素抵抗(225)。SIRT5-KO 小鼠的实验结果表明,至少在正常条件下,SIRT5对细胞代谢不是可有可无的。随后的研究已经显示出有希望的结果。在人类中,SIRT5基因在 NAFLD 患者(222例)肝脏中的表达减少,而 SIRT5在脂肪组织中的表达与胰岛素敏感性呈正相关(226例)。利用亲和富集和无标记的定量蛋白质组学,Nishida 等人研究了 sirt5调控的赖氨酸丙二酰基组(227)。通路分析证实糖异生和糖酵解是 sirt5调节的丙二酰化蛋白(227)中最富集的通路。SIRT5通过赖氨酸184(227)的脱孤反应调节糖酵解酶甘油醛磷酸脱氢酶(GAPDH)。根据这些结果,SIRT5可能在调节葡萄糖和脂质代谢和保持胰岛素敏感性方面发挥关键作用。线粒体特异性去乙酰化酶基因敲除小鼠没有明显的代谢异常,提示线粒体去乙酰化酶作为营养传感器来维持能量稳态。

SIRT6 and Insulin-Sensitive Organs

SIRT6与胰岛素敏感器官

SIRT6 Regulates Adipogenesis, Lipid Metabolism and Thermogenesis in Adipose Tissue

SIRT6调节脂肪组织的脂肪生成、脂质代谢和产热

SIRT6 expression is decreased in adipose tissue of db/db mice but increased in adipose tissue of human individuals with weight loss (228229), suggesting that SIRT6 plays a role in adipose tissue. Chen et al. (230) demonstrated that SIRT6 is required for mitotic clonal expansion during adipogenesis by inhibiting expression of kinesin family member 5C (KIF5C) and subsequent increasing CK2 kinase activity. Sirt6 transgenic mice exhibit resistance to HFD-induced obesity and insulin resistance (231). Conversely, fat-specific Sirt6knockout increases blood glucose levels and hepatic steatosis, and sensitizes mice to HFD-induced obesity and insulin resistance (5960232). SIRT6 overexpression downregulates a set of PPARγ target genes that are involved in lipid metabolism, lipid transport and adipogenesis (231). Especially, SIRT6 decreases expressions of ANGPTL4, a negative regulator of lipoprotein lipase, and diglyceride acyltransferase 1 (DGAT1), a key enzyme in triglycerides synthesis, leading to the increased serum triglyceride clearance and reducing triglyceride synthesis in adipose tissues (231). Sirt6 deletion decreases FoxO1 transcriptional activity by increasing its acetylation and phosphorylation and reduces expression of adipose triglyceride lipase (ATGL), a key lipolytic enzyme, reducing lipolysis (59). Fat-specific Sirt6 knockout not only induces obesity and insulin resistance but also impairs the thermogenic function of brown adipocytes (232). Yao et al. (232) found Sirt6 deletion decreases ATF2 binding to the PGC-1α promoter, leading to reducing the expression of PGC-1α and PGC-1α target thermogenic genes.

SIRT6在 db/db 小鼠脂肪组织中的表达减少,而在体重减轻的人体脂肪组织中的表达增加(228,229) ,提示 SIRT6在脂肪组织中起作用。Chen 等(230)证明,SIRT6通过抑制 kinesin 家族成员5C (KIF5C)的表达和随后增加 CK2激酶活性,在脂肪发生过程中促进有丝分裂克隆扩增。Sirt6转基因小鼠表现出对 hfd 诱导的肥胖和胰岛素抵抗(231)的抵抗。相反,脂肪特异性 Sirt6基因敲除增加血糖水平和肝脏脂肪变性,并使小鼠对 hfd 诱导的肥胖和胰岛素抵抗敏感(59,60,232)。SIRT6的过度表达下调了一组 ppar 靶基因,这些基因参与了脂质代谢、脂质转运和脂肪生成(231)。尤其是 SIRT6降低了血清中血管生成素样蛋白(ANGPTL4)和甘油二酯酰基转移酶(DGAT1)的表达,这是脂蛋白脂肪酶的负调节因子,而甘油二酯酰基转移酶1是甘油三酯合成的关键酶,它能增加血清甘油三酯清除率,减少脂肪组织中甘油三酯的合成。Sirt6缺失通过增加 FoxO1的乙酰化和磷酸化作用降低 FoxO1的转录活性,降低脂肪酶 ATGL 的表达,减少脂肪分解(59)。脂肪特异性 Sirt6基因敲除不仅引起肥胖和胰岛素抵抗,而且还损害棕色脂肪细胞的产热功能(232)。姚等人(232)发现 Sirt6缺失降低了 ATF2与 pgc-1启动子的结合,导致 pgc-1和 pgc-1靶向产热基因的表达减少。

SIRT6 Represses Gluconeogenesis and Lipid Accumulation in the Liver

SIRT6抑制肝脏糖异生和脂质积累

The hepatic SIRT6 level is reduced in obese/diabetic mice and gluconeogenic genes were higher in Sirt6-deficient livers whereas ectopic re-expression of SIRT6 suppressed gluconeogenesis and normalizes glycemia (228233). Mechanistically, SIRT6 interacts with and increases the activity of general control non-repressed protein 5 (GCN5), an acetyltransferase, which, in turn, catalyzes the acetylation of PGC-1α, suppressing gluconeogenic gene expression such as phosphoenolpyruvate carboxykinase C (PEPCK-C) and glucose 6-phosphatase, and resulting in repression of hepatic glucose output (228). p53 directly activates expression of SIRT6, which subsequently interacts with and deacetylates FoxO1, leading to FoxO1 export to the cytoplasm, and finally, reduce the expression of gluconeogenetic genes such as glucose 6-phosphatase alpha and phosphoenolpyruvate carboxykinase 1 (234). Human fatty liver samples exhibited significantly lower levels of SIRT6 than normal controls and liver-specific deletion of Sirt6 in mice causes increased glycolysis, triglyceride synthesis, reduced β-oxidation, and leads to liver steatosis (235). Rosiglitazone, an agonist of PPARγ, increases the expression of SIRT6, PGC-1α, and FoxO1, and AMPK phosphorylation in rat liver and ameliorates hepatic lipid accumulation (236). Sirt6 knockdown abolished the effects of rosiglitazone (236), suggesting Sirt6 at least partly mediates the metabolic effects of rosiglitazone. Altogether, those evidence suggest that SIRT6 significantly participates in glucose and lipid metabolism in the liver.

肥胖/糖尿病小鼠肝脏 SIRT6水平降低,SIRT6缺陷肝脏糖异生基因表达增高,而 SIRT6异位再表达抑制糖异生和正常血糖(228,233)。机制上,SIRT6与一般控制非抑制蛋白5(GCN5)相互作用并增加其活性,GCN5是一种乙酰化转移酶,它反过来催化 pgc-1的乙酰化,抑制磷酸烯醇丙酮酸羧化激酶 c (PEPCK-C)和葡萄糖6- 磷酸酶等葡萄糖异生基因的表达,导致肝糖输出(228)的抑制。P53直接激活 SIRT6的表达,随后与 FoxO1相互作用和去乙酰化,导致 FoxO1输出到细胞质中,最终降低葡萄糖6-alpha 和磷酸烯醇丙酮酸羧化激酶1(234)等糖异生基因的表达。人类脂肪肝标本的 SIRT6水平显著低于正常对照组,小鼠肝特异性 SIRT6缺失导致糖酵解增加、甘油三酯合成增加、氧化减少,并导致肝脏脂肪变性(235)。Ppar 激动剂罗格列酮可增加 SIRT6、 pgc-1和 FoxO1的表达,使 AMPK 磷酸化,抑制肝脂质积累(236)。Sirt6基因敲除消除了罗格列酮(236)的作用,提示 Sirt6至少部分介导了罗格列酮的代谢效应。总之,这些证据表明 SIRT6显著参与了肝脏中的葡萄糖和脂质代谢。

SIRT6 Increases Insulin Sensitivity in the Skeletal Muscle

SIRT6增加骨骼肌胰岛素敏感性

SIRT6 also regulates metabolic homeostasis in the skeletal muscle. Sirt6 transgenic mice show enhanced insulin sensitivity in skeletal muscle and exhibit enhanced insulin-induced activation of Akt in the gastrocnemius (153). By contrast, skeletal muscle-specific Sirt6 ko mice exhibit impaired glucose homeostasis and insulin sensitivity, attenuating whole-body energy expenditure (237). Mechanistically, Sirt6 deletion decreases AMPK activity and subsequently decreases the expression of genes involved in glucose and lipid uptake, fatty acid oxidation, and mitochondrial oxidative phosphorylation (237). Further studies are needed to elucidate the direct mechanism underlying SIRT6 function in skeletal muscle.

SIRT6还调节骨骼肌的代谢稳态。Sirt6转基因小鼠骨骼肌胰岛素敏感性增强,腓肠肌 Akt 活化增强(153)。相比之下,骨骼肌特异性 Sirt6 ko 小鼠表现出葡萄糖稳态和胰岛素敏感性受损,减少了全身能量消耗(237)。机制上,Sirt6缺失降低了 AMPK 活性,随后降低了与葡萄糖和脂肪摄取、脂肪酸氧化和线粒体氧化磷酸化相关的基因的表达。进一步的研究需要阐明 SIRT6功能的直接机制在骨骼肌。

SIRT7

SIRT7 Regulates Fatty Acid Metabolism in Adipose Tissues

SIRT7调节脂肪组织中的脂肪酸代谢

SIRT7 is the least characterized Sirtuin of the seven mammalian Sirtuins. SIRT7 protein levels are high in the liver, spleen, and testis, whereas are low in the muscle, heart, and brain of mice (16). In human, Sirt7 mRNA is expressed in various tissues (10). Recent reports clarify the important roles of SIRT7 in a variety of biological processes including DNA repair, chromatin assembly, and aging. However, the role of SIRT7 in metabolism remains largely unknown. The expression of Sirt7 mRNA level is upregulated in adipose tissues of obese patients (238). In HFD-fed mice, Sirt7 knockout decreased the expression of the fatty acid transporter CD36 in WAT (239). In addition, Sirt7 knockout led to an increase of thermogenesis along with increased expression of UCP1 and DIO2 in BAT (239). These results suggest SIRT7 regulates lipid metabolism in adipocytes. Recently, Fang al et. found that SIRT7 restricts SIRT1 activity by preventing SIRT1 auto-deacetylation, and increasing SIRT1 activity in Sirt7-KO mice blocks PPARγ and adipocyte differentiation, thereby decreases the accumulation of white fat (240241). Together, these findings implicate the important role of SIRT7 in the regulation of fatty acid metabolism.

SIRT7是7种哺乳动物 Sirtuin 中特征最少的一种 Sirtuin。SIRT7蛋白质在肝脏、脾脏和睾丸中含量高,而在小鼠的肌肉、心脏和大脑中含量低。在人体内,sirt7mrna 在各种组织中都有表达(10)。最近的报道阐明了 SIRT7在包括 DNA 修复、染色质组装和衰老在内的各种生物过程中的重要作用。然而,SIRT7在新陈代谢中的作用仍然很大程度上未知。Sirt7 mRNA 在肥胖患者脂肪组织中的表达上调(238例)。在 HFD-fed 小鼠中,Sirt7基因敲除降低了脂肪酸转运蛋白 CD36在 WAT (239)中的表达。此外,Sirt7基因敲除导致热生成增加,同时增加了在 BAT (239)中 UCP1和 DIO2的表达。这些结果提示 SIRT7调节脂肪细胞中的脂质代谢。最近,方等人。结果表明,SIRT7通过抑制 SIRT1自身去乙酰化,抑制 SIRT1活性,增加 SIRT1活性,阻断 ppar 和脂肪细胞的分化,从而减少白色脂肪的积累(240,241)。总之,这些发现暗示了 SIRT7在脂肪酸代谢调节中的重要作用。

SIRT7 Regulates Fatty Acid and Glucose Metabolism in the Liver

SIRT7调节肝脏脂肪酸和葡萄糖代谢

Up to now, there are three studies linking SIRT7 to the liver lipid metabolism using independently generated mouse models. Shin et al. reported that Sirt7-KO mice developed steatosis resembling human fatty liver disease (242). Selectively overexpression of SIRT7 in the liver of Sirt7-KO mice via adeno-associated virus 8 (AAV8)-mediated gene transfer prevents the development of fatty liver (242). The authors found expressions of inflammatory markers and lipogenic genes are increased in Sirt7-deficient livers, and they clarified the underlying mechanism as SIRT7 repressing the expression of ribosomal proteins through decreasing Myc activity and further suppressing ER stress (242). Ryu et al. generated a different Sirt7-KO mouse by deleting exons 6-9, and observed more general metabolic defects including hepatic microvesicular steatosis, increased blood lactate levels, reduced exercise performance, cardiac dysfunction and age-related hearing loss induced by multisystemic mitochondrial dysfunction (127). Mechanistically, SIRT7 deacetylates GABPβ1, thereby enables it to form the transcriptionally active GABPα/GABPβ heterotetramer, and then promotes mitochondria function (127). Another study has the opposite result. Yoshizawa et al. reported that Sirt7-KO mice, deleting exons 4-9, are resistant to HFD induced fatty liver, obesity, and glucose intolerance (239). TR4 is a nuclear receptor involved in lipid metabolism and its target genes increase fatty acid uptake and triglyceride synthesis and storage (243). Hepatic SIRT7 was reported to increase TR4 expression through binding with DCAF1/DDB1/CUL4B E3 ubiquitin ligase complex and inhibiting TR4 degradation (239). It is difficult to explain the divergence of three Sirt7-KO mouse models with different genetic background. Liver-specific knockout or Sirt7 transgene mouse model may be helpful to clarify the role of SIRT7 in liver lipid metabolism (239242). In addition to lipid metabolism, SIRT7 is involved in glucose metabolism. SIRT7 regulates acetylation at the K323 site of phosphoglycerate kinase 1 (PGK1), an important enzyme in glycolysis, decreases PGK1 enzyme activity and inhibits glycolysis in liver cancer cells (244). Yoshizawa et al. Found that Sirt7-KO mice show decreased expression of the hepatic glucose-6-phosphatase catalytic subunit (G6PC), a key gluconeogenic enzyme, and resistance to glucose intolerance (239). Mechanistically, glucose deprivation stimulates SIRT7 binding to the promoter of G6PC, and deacetylating H3K18 in the G6PC promoter, which results in elevated G6PC expression and promotion of hepatic gluconeogenesis (245).

到目前为止,已经有3项研究利用独立生成的小鼠模型将 SIRT7与脂质代谢联系起来。Shin 等人报告说,Sirt7-KO 小鼠出现了类似人类脂肪肝疾病的脂肪变性(242)。通过腺相关病毒8(AAV8)介导的基因转移选择性过量表达 SIRT7-ko 小鼠肝脏对脂肪肝的预防作用(242)。作者发现 SIRT7缺陷肝脏中炎症标志物和脂肪基因的表达增加,并阐明了 SIRT7通过降低 Myc 活性和进一步抑制 ER 应激抑制核糖体蛋白表达的潜在机制。Ryu 等人通过删除第6-9外显子产生了另一种 Sirt7-KO 小鼠,并观察到更多的一般代谢缺陷,包括肝脏微泡脂肪变性、血乳酸水平升高、运动能力下降、心脏功能障碍和多系统线粒体功能障碍引起的年龄相关性听力损失(127)。SIRT7机制性地去乙酰化 gabp1,从而使其形成转录活性的 gabp/gabp 异质四聚体,进而促进线粒体功能(127)。另一项研究得出了相反的结果。Yoshizawa 等人报告说,Sirt7-KO 小鼠,删除第4-9外显子,对 HFD 诱导的脂肪肝、肥胖和葡萄糖耐受不良有抵抗力(239)。TR4是一种核受体,参与脂质代谢和它的目标基因增加脂肪酸摄取和甘油三酯的合成和储存(243)。据报道,SIRT7通过与 DCAF1/DDB1/CUL4B E3泛素连接酶复合物结合,抑制 TR4降解,从而增加 TR4的表达。三种遗传背景不同的 Sirt7-KO 小鼠模型的差异难以解释。肝脏特异性基因敲除或 SIRT7转基因小鼠模型可能有助于阐明 SIRT7在肝脏脂质代谢(239,242)的作用。除了脂质代谢,SIRT7还参与了葡萄糖代谢。SIRT7调节糖酵解过程中一种重要的酶-磷酸甘油酸激酶1(PGK1)的 K323位点的乙酰化,降低 PGK1酶的活性,抑制肝癌细胞的糖酵解(244)。吉泽等人。发现 Sirt7-KO 小鼠肝葡萄糖 -6- 磷酸酶催化亚基(G6PC)的表达减少,这是一种关键的葡萄糖异生酶,并对葡萄糖耐受不良(239)有抵抗力。机制上,缺糖刺激 G6PC 启动子结合 SIRT7和 G6PC 启动子去乙酰化 H3K18,导致 G6PC 表达升高,促进肝糖异生(245)。

Sirtuins in Aging-related Metabolic Defects

去乙酰化酶在衰老相关代谢缺陷中的作用

Aging is a complex process accompanied by the declines in basal metabolic rate and physical activity. Aging is one of the major risk factors contributing to the development of insulin resistance, obesity, T2DM and metabolic syndrome (246). During the aging process, chronic inflammation and mitochondria dysfunction in pancreatic β cells and insulin-sensitive organs have been demonstrated to be major mechanisms linking aging and insulin resistance (247250). As mentioned above, Sirtuins play important roles in regulating inflammation and mitochondria function. Sirtuins are critically involved in lifespan and healthspan. Deficiency of Sirtuins (SIRT1, SIRT6, and SIRT7) is associated with shortened lifespan and metabolic diseases (251). Our recent evidence also demonstrated that SIRT2 deficiency also facilitated the aging-related development of cardiac dysfunction, including hypertrophy and fibrosis (252). By contrast, germline or cell-specific overexpression of SIRT1 or SIRT6 were reported to expand lifespan and defense metabolic diseases in insulin-dependent and independent manners (253255).

衰老是一个复杂的过程,伴随着基础代谢率和身体活动的减少。老化是导致胰岛素抵抗、肥胖、2型糖尿病和代谢症候群的主要危险因素之一。在老化过程中,胰腺细胞和胰岛素敏感器官中的慢性炎症和线粒体功能障碍被证明是老化和胰岛素抵抗的主要机制(247-250)。如上所述,去乙酰化酶在调节炎症和线粒体功能方面发挥重要作用。去乙酰化酶与寿命和健康寿命密切相关。缺乏 Sirtuins (SIRT1,SIRT6和 SIRT7)与缩短的寿命和代谢疾病(251)有关。我们最近的证据还表明,SIRT2缺乏也促进了与年龄有关的心脏功能障碍的发展,包括肥大和纤维化(252)。相比之下,SIRT1或 SIRT6的种系或细胞特异性过表达可以延长寿命和防御胰岛素依赖和独立方式的代谢性疾病(253-255)。

Sirtuin-targeted strategies show promising in repressing aging-related insulin resistance and metabolic diseases. For instance, the SIRT1 activator SRT1720 extends lifespan and improves the health of mice fed a standard diet (256163). It is well established that caloric restriction (CR), the Sirtuin activator, is an effective and reliable means to defense against aging and extend the lifespan and healthspan of mammals, including monkeys (257). Activation of vascular SIRT1 by CR leads to the repressing of aging-related metabolic vascular diseases, including atherosclerosis and aortic aneurysm (258260). In human studies, CR also can reduce insulin resistance significantly and delay the onset of metabolic diseases (261262). Although the mechanisms by which CR extend lifespan are not fully understood, Sirtuins have been implicated to mediate beneficial effects of CR on aging (263). Notably, the CR mimetics (metformin, resveratrol, rapamycin) could expand lifespan and repress diseases related to insulin resistance in rodents partially through activation of Sirtuins (257264). Our data showed that SIRT2 contributes to the effects of metformin on aging-related diseases, including cardiac remodeling (252). Currently, clinical trials investigating the anti-aging effects of metformin is undergoing (ClinicalTrials.gov Identifier: NCT02432287).

以去乙酰化酶为靶点的策略在抑制老化相关的胰岛素抵抗和代谢性疾病方面显示出良好的前景。例如,SIRT1激活剂 SRT1720延长寿命,改善了喂食标准饮食(256,163)的老鼠的健康状况。已经证实,限制卡路里(CR) ,Sirtuin 激活剂,是一种有效和可靠的手段,防御衰老,延长哺乳动物的寿命和健康跨度,包括猴子(257)。CR 激活血管 SIRT1可抑制衰老相关的代谢性血管疾病,包括动脉粥样硬化和主动脉瘤(258-260)。在人体研究中,CR 还能显著降低胰岛素抵抗,延缓代谢性疾病的发生(261,262)。虽然 CR 延长寿命的机制还不完全清楚,但是 Sirtuins 参与了 CR 对衰老的有益影响(263)。值得注意的是,CR 模型药物(二甲双胍、白藜芦醇、雷帕霉素)可以通过激活 Sirtuins (257,264)延长寿命,部分抑制与胰岛素抵抗有关的疾病。我们的数据表明,SIRT2有助于二甲双胍对衰老相关疾病的影响,包括心脏重构(252)。目前,研究二甲双胍抗衰老作用的临床试验正在进行中( clinicaltrials.gov 标识符: NCT02432287)。

Importantly, the Sirtuins do not function in individual metabolic organs or cell types alone during aging. Instead, the Sirtuins orchestrate the crosstalk between different organs or between different cell types within the local microenvironmental niche to maintain metabolic homeostasis and prevent against insulin resistance. The SIRT1 activator SRT3025 provides atheroprotection in Apoe−/− mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression (265). Resveratrol activates duodenal SIRT1 to initiate a gut-brain-liver neuronal axis that improves hypothalamic insulin sensitivity in rats (183). SIRT1 in intestinal stem cells also contributes to the protection roles of caloric restriction on aging (266). In addition, SIRT3 activation by nitrite and metformin improves insulin sensitivity in skeletal muscle and normalizes pulmonary hypertension associated with heart failure with preserved ejection fraction (267). Sirtuins also regulate inflammatory cells within the local microenvironmental niches to regulate insulin resistance in an autocrine or paracrine manner (417980).

重要的是,去乙酰化酶在衰老过程中并不仅仅在单个代谢器官或细胞类型中发挥作用。相反,去乙酰化酶协调不同器官之间或局部微环境小生境中不同细胞类型之间的相互干扰,以维持代谢稳态并防止胰岛素抵抗。SIRT1激活剂 SRT3025通过减少肝 Pcsk9分泌和增强 Ldlr 表达(265) ,为 Apoe/-小鼠提供动脉粥样硬化保护。白藜芦醇激活十二指肠 SIRT1启动肠脑肝神经元轴,改善大鼠下丘脑胰岛素敏感性(183)。肠干细胞中的 SIRT1也有助于热量限制对衰老的保护作用(266)。此外,通过亚硝酸盐和二甲双胍激活 SIRT3可以提高骨骼肌的胰岛素敏感性,并且通过保存肺部高压射出分率使心力衰竭患者的胰岛素敏感性恢复正常。Sirtuins 也调节局部微环境龛内的炎症细胞,以自分泌或旁分泌方式调节胰岛素抵抗(41,79,80)。

Therefore, targeting Sirtuins could be a promising strategy for improvement of insulin sensitivity and metabolic status of the whole body. However, activation of Sirtuins alone may not archive the biggest benefits because of the exhaustion of the endogenous NAD. Sirtuin activator in supplement with NAD precursor may represent a better therapeutic strategy for repressing aging-related insulin resistance and metabolic diseases.

因此,靶向性去乙酰化酶可能是改善胰岛素敏感性和全身代谢状态的一种有前途的策略。然而,由于内源性 NAD 的耗竭,仅仅激活去乙酰化酶可能不能保存最大的益处。去乙酰化酶激活剂联合 NAD 前体可能是抑制衰老相关的胰岛素抵抗和代谢性疾病的一种较好的治疗策略。

Concluding Remarks

结语

Insulin resistance is a critical pathological feature of obesity and metabolic syndrome and plays a key role in the pathogenesis of T2DM and attendant cardiovascular complications. Moreover, insulin resistance provides a therapeutic strategy to prevent, delay or treat T2DM, obesity, and metabolic syndrome by improving insulin sensitivity. Although insulin resistance is a complex metabolic disorder that has remained poorly understood, Sirtuin family members are involved in the potential cellular mechanisms of the pathogenesis of insulin resistance. According to accumulating evidence in the past decades, Sirtuin family members have emerged as a nutrient sensor to maintain energy homeostasis. Cellular and animal studies have demonstrated that Sirtuins play an important role in regulating glucose and lipids by modulating crucial enzymes in metabolic pathways and interfering with inflammation, oxidative stress, mitochondrial dysfunction, ER stress, and the insulin signaling pathway.

胰岛素抵抗是肥胖和代谢症候群的重要病理特征,在2型糖尿病及相关心血管并发症的发病机制中起着关键作用。此外,胰岛素抵抗提供了一种治疗策略,可以通过改善胰岛素敏感性来预防、延缓或治疗2型糖尿病、肥胖和代谢症候群。虽然胰岛素抵抗是一个复杂的代谢疾病,至今仍然知之甚少,Sirtuin 家族成员参与了胰岛素抵抗发病机制的潜在细胞机制。根据过去几十年积累的证据,Sirtuin 家族成员已经成为一种维持能量平衡的营养传感器。细胞和动物研究表明,去乙酰化酶通过调节代谢途径中的关键酶,干扰炎症、氧化应激、线粒体功能障碍、内质网应激和胰岛素信号通路,在调节血糖和血脂方面发挥重要作用。

Sirtuins respond to environmental (diet and lifestyle) or metabolic (obesity, fasting, and diabetes) insults at mRNA and protein levels in insulin-sensing organs (268269). The roles of Sirtuins in regulating glucose and lipid metabolism as well as insulin resistance in liver, adipose tissue, and skeletal muscle make their importance in regulating metabolic diseases, including T2DM and diabetic complications (269).

Sirtuins 对环境(饮食和生活方式)或新陈代谢(肥胖、禁食和糖尿病)的信使核糖核酸和胰岛素感应器官的蛋白质水平作出反应(268,269)。Sirtuins 在调节葡萄糖和脂质代谢以及肝脏、脂肪组织和骨骼肌的胰岛素抵抗中的作用使它们在调节代谢性疾病,包括 T2DM 和糖尿病并发症中的重要性(269)。

Nevertheless, many additional studies are needed.

然而,还需要许多其他的研究。

1. Different Sirtuins may have the same downstream targets, such as FoxO3a, FoxO1, PGC-1α, and GDH, and there is cross-talk among Sirtuin family members (11756270). How do different Sirtuin members coordinate to regulate the same downstream targets?

1.不同的 Sirtuin 可能具有相同的下游目标,如 FoxO3a、 FoxO1、 pgc-1和 GDH,并且 Sirtuin 家族成员之间存在串扰(117,56,270)。不同的 Sirtuin 成员如何协调来调节相同的下游目标?

2. The Sirtuin family comprises NAD+-dependent histone deacetylases; however, recent results have revealed that Sirtuin members can act in a deacetylase-independent manner (117). How can we determine the functions and activities of Sirtuins in addition to their deacetylation function in insulin resistance?

图2。Sirtuin 家族包括 NAD + 依赖的组蛋白去乙酰化酶,然而,最近的研究结果表明 Sirtuin 成员可以以一种与去乙酰化酶无关的方式发挥作用(117)。除了去乙酰化作用外,如何确定去乙酰化酶在胰岛素抵抗中的作用和活性?

3. In addition to Sirtuins, there are other epigenetic modification enzymes, including SUV39H1 and EZH2 are involved in insulin resistance and T2DM (271276). There is an interaction between SUV39H1 and Sirtuins, including SIRT1, SIRT3, and SIRT7 (277281). EZH2 is reportedly the deacetylating substrate of SIRT1 (282283). SIRT2 negatively regulates JMJD2A expression in human non-small cell lung cancer tissues (284). Is JMJD2A involved in insulin resistance? In the condition of insulin resistance, how do these epigenetic modification enzymes influence each other and consequently act on insulin sensitivity?

图3。除了 Sirtuins,还有其他的表观遗传修饰酶,包括 SUV39H1和 EZH2参与了胰岛素抵抗和 T2DM (271-276)。SUV39H1和 Sirtuins 之间存在相互作用,包括 SIRT1、 SIRT3和 SIRT7(277-281)。据报道 EZH2是 SIRT1(282,283)的去乙酰化底物。SIRT2对人非小细胞肺癌组织 JMJD2A 表达的负性调节(284)。JMJD2A 与胰岛素抵抗有关吗?在胰岛素抵抗的情况下,这些表观遗传修饰酶是如何相互影响从而作用于胰岛素敏感性的?

4. Obesity, insulin resistance, and T2DM are aging-related abnormalities. Sirtuins, especially SIRT1, SIRT2, and SIRT6, are characterized as protectors of aging and aging-related diseases. Whether the promotive effect of aging by the decline of Sirtuin activity is involved in insulin resistance deserves further investigation. In addition, cell senescence-induced organ dysfunction and aging (senescaging) are common during physiological and pathological aging processes (268). Selective elimination of senescent cells, or senolysis, was reported to delay aging and aging-related metabolic diseases including congestive decline, atherosclerosis, cardiac diseases, and osteoarthritis (285291). However, it remains to elucidate that what are the physiological and pathological functions of cellular senescence in organs during aging and that whether Sirtuins regulate senescaging in insulin resistance and healthy conditions.

图4。肥胖、胰岛素抵抗和2型糖尿病是与衰老有关的异常。Sirtuins,特别是 SIRT1,SIRT2,和 SIRT6,被认为是老化和老化相关疾病的保护因子。Sirtuin 活性下降对衰老的促进作用是否与胰岛素抵抗有关值得进一步研究。此外,细胞衰老引起的器官功能障碍和衰老(衰老)是常见的生理和病理衰老过程(268)。选择性消除衰老细胞,或衰老,据报道,延缓衰老和衰老相关的代谢疾病,包括充血性衰退,动脉粥样硬化,心脏病和骨关节炎(285-291)。然而,衰老过程中器官细胞衰老的生理和病理功能以及去乙酰化酶是否在胰岛素抵抗和健康条件下调节衰老仍有待进一步研究。

Author Contributions

作者贡献

All authors listed have made a substantial, direct and intellectual contribution to the work. SZ is responsible for literature collection and article draft. XT designed the Figures and revised the manuscript. H-ZC is the leading principal investigator who directed the study and data analysis, and prepared the manuscript. All authors approved publication of this work.

所有列出的作者都对这部作品做出了实质性的、直接的和智力上的贡献。负责文献收集和文章起草工作。文字部分设计了图形,修改了稿件。是指导这项研究和数据分析并准备手稿的主要学术带头人。所有作者都同意出版这部作品。

Conflict of Interest Statement

利益冲突声明

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

作者宣称,这项研究是在没有任何商业或金融关系的情况下进行的,这种关系可能被解释为潜在的利益冲突。

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