Regulation of Hepatic Lipid Accumulation and Insulin Resistance

 描述(申请人提供)：非酒精性脂肪性肝病(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。大多数关于肝脏脂肪变性的研究都集中在参与从头脂肪生成的酶。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(脂肪甘油三酯脂肪酶)及其辅活化子CGI-58(比较基因鉴定-58)。我们以前的研究已经确定G0S2(G0/G1 Switch gene 2)是ATGL的内源性抑制因子，并提供了令人信服的证据，表明G0S2的差异表达在调节脂肪分解、脂肪-肝脏FA流量和肝脏脂质含量方面起着至关重要的作用。有趣的是，我们已经获得了初步证据，G0S2在甘油磷酸合成甘油三酯的途径中也独立于ATGL发挥作用。该应用的目的是进一步探讨G0S2在肝脏脂肪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生发展。这些研究的假设是，G0S2通过作用于肝脏X受体α(LxRα)的下游，是一种同时具有脂解抑制和溶血磷脂酸酰基转移酶活性的双功能蛋白。虽然这两种功能都会导致禁食期间和高脂肪、高碳水化合物喂养导致肝脏脂肪变性，但G0S2的S作为LPAAT的作用促进了肝脏中磷脂酸(PA)和二酰甘油(DG)的合成，并导致其对饮食诱导肥胖小鼠的不利影响。 这项拟议研究的基本原理是，确定G0S2在调节肝脂积聚中的作用将提供对NAFLD和相关疾病的病因的重要洞察，从而促进营养或药物治疗的发展。这一假说将通过三个特定的目标来验证：1)表征LXRLXRLPAAT-G0S2轴及其在肝脂代谢中的作用；2)确定G0S2作为促进肝脏TG蓄积的LPAAT的生理学相关性；以及3)确定G0S2在饮食诱导的胰岛素抵抗中不依赖于α的作用。我们将结合我们实验室建立的细胞生物学和生理学方法的使用，以及现有的G0S2、LXRα或ATGL缺陷的独特动物模型，进行功能获得和功能丧失的研究。这些研究具有创新性，因为它们集中在一种独特的甘油三酯合成和水解的双重功能调节器在肝脏脂肪变性和胰岛素抵抗的发生发展中的作用。了解肝脏甘油三酯代谢的调节具有重要意义，因为它不仅影响NAFLD的治疗，而且将推动与肥胖相关的能量代谢领域的发展。

 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.