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（由适用提供）：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从头脂肪生成的酶上。然而，新兴数据还表明，蛋白质的关键贡献，这些蛋白质的蛋白质贡献了肝内脂解，包括关键的甘油三酸酯水解ATGL（脂肪甘油三酸酯脂肪酶）及其共激活剂CGI-58（比较基因鉴定-58）。我们以前的研究已将G0S2（G0/G1开关基因2）鉴定为ATGL的内源性抑制剂，并提供了令人信服的证据，表明G0S2的差异表达在减少脂肪脂肪溶解，脂肪肝FA磁通和肝脂质脂质含量中起着至关重要的作用。有趣的是，我们获得了初步证据，即G0S2在磷酸甘油途径中也独立于ATGL进行TG合成。该应用的目的是进一步探索G0S2在肝脂质和能量代谢中的作用，以及与肥胖相关的肝脂肪变性和胰岛素抵抗的发展。拟议研究的假设是，通过对肝X受体-α（LXRα）的下游作用，G0S2是一种双功能蛋白，具有脂解抑制剂和溶血磷脂酸酰基转移酶（LPAAT）的活性。尽管这两种功能在禁食过程中有助于肝脏脂肪变性，并响应高脂和高碳水化合物喂养，但G0S2作为LPAAT的作用促进了磷脂酸（PA）和肝甘油（DG）的合成，并在肝脏中促进了其在饮食中造成饮食效果的有害作用（DIO）。 拟议研究的理由是，确定G0S2在介导肝脂质积累中的作用将为NAFLD和相关疾病的病因提供重大见解，从而促进营养或药物疗法的发展可能性。该假设将使用三个特定目的进行检验：1）表征LXRα-G0S2轴及其在肝脂质代谢中的作用； 2）确定G0S2作为促进肝Tg积累的LPAAT的生理相关性； 3）确定G0S2在饮食诱导的胰岛素抵抗中的非依赖性作用。我们将通过将在实验室中建立的细胞生物学和物理方法与缺乏G0S2，LXRα或ATGL缺乏的独特动物模型相结合，可以同时进行增益和功能丧失研究。这些研究之所以创新，是因为它们专注于独特的双重功能的作用，了解肝素TG代谢的调节是重要的，因为它不仅会影响NAFLD的治疗方法，而且还会推进与肥胖有关的能量代谢领域。