人体是如何产生甘油三酯的

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How the body makes triglycerides

Date: 日期:May 13, 2020 2020年5月13日Source: 来源:Baylor College of Medicine 贝勒医学院Summary: 摘要:Researchers discovered the 3D structure and mode of action of DGAT1, the enzyme that synthesizes triglycerides. 研究人员发现了合成甘油三酯的酶 DGAT1的三维结构和作用方式


Doctors regularly warn their patients that having high levels of triglycerides, a major dietary fat, can increase the risk of heart disease, diabetes, obesity and fatty liver disease. There is considerable interest in finding novel ways to effectively regulate triglycerides in the blood to help manage these potentially life-threatening common conditions.

医生经常警告他们的病人,高水平的甘油三酯,一种主要的饮食脂肪,可以增加患心脏病,糖尿病,肥胖症和脂肪肝疾病的风险。人们对于寻找新的方法有效地调节血液中的甘油三酯以帮助管理这些潜在的威胁生命的常见情况非常感兴趣。

Now, researchers at Baylor College of Medicine, Princeton University and Texas A&M University are closer to achieving this goal after discovering the 3-D structure and mode of action of diacylglycerol O-acyltransferase-1 (DGAT1), the enzyme that synthesizes triglycerides and also is required for human dietary fat absorption and storage. DGAT1 is a known target to treat obesity and other metabolic diseases, so having a detailed understanding of what DGAT1 looks like and how it works opens opportunities for designing novel strategies for managing these conditions. The findings are published in the journal Nature.

现在,贝勒医学院、普林斯顿大学和德州农工大学的研究人员在发现甘油二酯 o- 酰基转移酶 -1(DGAT1)的3-D 结构和作用方式后,更接近于实现这一目标。DGAT1是治疗肥胖和其他代谢性疾病的已知靶点,因此详细了解 DGAT1是什么样子以及它是如何工作的,为设计新颖的策略来管理这些疾病提供了机会。研究结果发表在《自然》杂志上。

“DGAT1 is a particularly interesting enzyme because it synthesizes triglycerides, which are the main component of hard fat, the type of fat usually found in the belly or midsection in our body. Triglycerides also are part of the particles that transport cholesterol — high-density lipoproteins (HDL, or ‘good cholesterol’), and low-density and very-low-density lipoproteins (LDL and VLDL, or ‘bad cholesterols’),” said co-corresponding author Dr. Ming Zhou, Ruth McLean Bowman Bowers Professor in Biochemistry in the Department of Biochemistry and Molecular Biology at Baylor. “Learning to regulate this enzyme can help regulate fat synthesis and potentially manage related conditions.”

“ DGAT1是一种特别有趣的酶,因为它合成甘油三酯,这是硬脂肪的主要组成部分,这种脂肪通常存在于我们的腹部或上腹部。甘油三酯也是运输胆固醇的颗粒的一部分——高密度脂蛋白(HDL,或‘好胆固醇’) ,以及低密度和非常低密度的脂蛋白(LDL 和 VLDL,或‘坏胆固醇’)。”。“学习调节这种酶可以帮助调节脂肪的合成,并可能控制相关的情况。”

Lie Wang, a graduate student in the Zhou lab, took the lead on this project. He applied cryo-electron microscopy, a technique that enables scientists to see how biomolecules move and interact as they perform their functions, to visualize the 3-D structure of DGAT1.

王,周实验室的一名研究生,领导了这个项目。他应用冷冻电子显微技术,使科学家能够看到生物分子在履行其功能时是如何运动和相互作用的,从而可视化 DGAT1的3-D 结构。

“This project was challenging because DGAT1 is embedded in biological membranes where it carries its function,” Wang said. “We also developed an enzymatic assay, or test, to monitor the activity of DGAT1 in real time. Thanks to the integration of high-quality structure and precise functional studies we were able to unveil the structure of this important enzyme and gain novel insights into the mechanism of action.”

“这个项目是具有挑战性的,因为 DGAT1被植入到生物膜中,在那里它承担着它的功能,”王说。“我们还开发了一种酶分析法,或者说测试法,来实时监测 DGAT1的活性。由于高质量的结构和精确的功能研究的结合,我们能够揭示这一重要酶的结构,并获得对作用机制的新见解。”

DGAT1 is located in the membrane of the endoplasmic reticulum, a cellular structure engaged in the synthesis of proteins and lipids.

1位于内质网的细胞膜上,这是一种参与蛋白质和脂质合成的细胞结构。

“It was exciting to discover that DGAT1 forms a large chamber inside the membrane, which was unexpected,” Wang said. “This ‘reaction chamber’ isolates a space within the membrane where the enzymatic synthesis of triglycerides takes place.”

“令人兴奋的是,我们发现 DGAT1在细胞膜内形成了一个很大的腔室,这是意想不到的,”王说。“这个‘反应室’隔离了膜内的一个空间,在这里酶促合成甘油三酯。”

“The reactants meet inside the chamber and that is where the reaction occurs. Then, the triglycerides bud-off the membrane in lipid droplets that carry them to where they are needed in the cell,” Zhou said. “Neither this 3-D structure of DGAT1 nor its mechanism of action were known before in such detail.”

“反应物在反应室内相遇,这就是反应发生的地方。然后,甘油三酯以脂滴的形式脱离细胞膜,带到细胞内需要它们的地方,”周说。“这种 DGAT1的三维结构及其作用机制以前都没有这么详细的了解。”

This study not only reveals the structure and mode of action of a human enzyme that is essential for proper human metabolism, but it also enables researchers to explore the effects of molecules that interact with DGAT1 and potentially regulate its activity.

这项研究不仅揭示了人体正常新陈代谢所必需的酶的结构和作用方式,而且还使研究人员能够探索与 DGAT1相互作用并可能调节其活性的分子的影响。


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