Regulation of Hepatic Lipid Accumulation and Insulin Resistance

肝脏脂质蓄积和胰岛素抵抗的调节

• 批准号: 9841676
• 负责人: Jun Liu
• 金额: $ 19.25万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9841676
• 关键词: Regulation; Hepatic; Lipid; Accumulation; Insulin

 DESCRIPTION (provided by applicant): Non-alcoholic fatty liver disease (NAFLD) and the progressive non-alcoholic steatohepatitis (NASH) are often associated with obesity, insulin resistance and coronary artery diseases. Most studies on hepatic steatosis have focused on enzymes involved in de novo lipogenesis. However, emerging data also point to critical contributions of proteins regulating intrahepatic lipolysis, including the key triglyceride hydrolae ATGL (adipose triglyceride lipase) along with its coactivator CGI-58 (Comparative Gene Identification-58). Our previous studies have identified G0S2 (G0/G1 Switch Gene 2) as an endogenous inhibitor of ATGL, and have provided compelling evidence that differential expression of G0S2 plays a crucial role in regulating adipose lipolysis, adipose-liver FA flux and hepatic lipid content. Interestingly, we have obtained preliminary evidence that G0S2 also functions independently of ATGL in the glycerol phosphate pathway for TG synthesis. The objective of this application is to further explore the roles of G0S2 in hepatic lipid and energy metabolism, and the development of obesity-associated hepatic steatosis and insulin resistance. The hypothesis of the proposed studies is that by acting downstream of the liver X receptor-α (LXRα), G0S2 is a dual-function protein that possesses activities of both a lipolytic inhibitor and a lysophosphatidic acid acyltransferase (LPAAT). While both functions contribute to hepatic steatosis during fasting and in response to high-fat and high-carbohydrate feeding, G0S2's role as a LPAAT promotes synthesis of phosphatidic acid (PA) and diacylglycerol (DG) in the liver and is responsible for its detrimental effect in mice with diet-induced obesity (DIO). The rationale for the proposed research is that identifying the role of G0S2 in mediating hepatic lipid accumulation will provide significant insight into the etiology of NAFLD and related disorders, thereby advancing the possibilities for development of nutritional or pharmaceutical therapies. The hypothesis will be tested using three specific aims: 1) to characterize the LXRα-G0S2 axis and its role in hepatic lipid metabolism; 2) to determine the physiologic relevance of G0S2 as a LPAAT in promoting hepatic TG accumulation; and 3) to determine the ATGL-independent role of G0S2 in diet-induced insulin resistance. We will perform both gain- and loss-of- function studies by combining the usage of cell biological and physiological approaches established in our laboratory with unique animal models deficient in G0S2, LXRα or ATGL that are available. These studies are innovative because they focus on the roles of a unique dual-function regulator of TG synthesis and hydrolysis in the development of hepatic steatosis and insulin resistance. Understanding how hepatic TG metabolism is regulated is significant because it not only impacts the treatment of NAFLD, but also will advance the field of energy metabolism as it relates to obesity.

 描述（由申请人提供）：非酒精性脂肪肝病（NAFLD）和进行性非酒精性脂肪性肝炎（NASH）通常与肥胖、胰岛素抵抗和冠状动脉疾病有关。大多数关于肝脂肪变性的研究都集中在参与脂肪变性的酶上。然而，新出现的数据也指出了调节肝内脂肪分解的蛋白质的关键作用，包括关键的甘油三酯水解酶 ATGL（脂肪）。我们之前的研究已经确定 G0S2（G0/G1 开关基因 2）是 ATGL 的内源性抑制剂，并提供了令人信服的证据表明 G0S2 的差异表达发挥着作用。 G0S2 在调节脂肪脂解、脂肪-肝脏 FA 通量和肝脂质含量方面发挥着至关重要的作用，但我们已经获得了初步证据表明 G0S2 也能独立发挥作用。 ATGL在TG合成的磷酸甘油途径中的作用本申请的目的是进一步探讨G0S2在肝脏脂质和能量代谢中的作用，以及肥胖相关的肝脏脂肪变性和胰岛素抵抗的发展的假设。 G0S2 是一种双功能蛋白，通过作用于肝脏 X 受体-α (LXRα) 的下游，具有脂解抑制剂和溶血磷脂酸的活性虽然这两种功能都会在禁食期间以及响应高脂肪和高碳水化合物喂养时导致肝脏脂肪变性，但 G0S2 作为 LPAAT 的作用会促进肝脏中磷脂酸 (PA) 和二酰甘油 (DG) 的合成，并且是其对饮食诱导肥胖（DIO）小鼠产生疼痛作用的原因。 拟议研究的基本原理是，确定 G0S2 在介导肝脏脂质积累中的作用将为 NAFLD 和相关疾病的病因学提供重要的见解，从而推进开发营养或药物疗法的可能性。该假设将使用三种方法进行检验。具体目标：1) 表征 LXRα-G0S2 轴及其在肝脏脂质代谢中的作用；2) 确定 G0S2 作为 LPAAT 在促进肝脏 TG 方面的生理相关性积累；3) 确定 G0S2 在饮食诱导的胰岛素抵抗中的独立于 ATGL 的作用，我们将通过结合我们实验室建立的细胞生物学和生理学方法来进行功能获得和丧失的研究。这些研究具有创新性，因为它们关注的是 TG 合成和水解的独特双功能调节剂在肝脂肪变性和胰岛素抵抗发展中的作用。肝脏TG代谢的调节具有重要意义，因为它不仅影响NAFLD的治疗，而且还将推进与肥胖相关的能量代谢领域。