? 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 point to critical contributions of proteins regulating intrahepatic lipolysis, including the key triglyceride hydrolase ATGL (adipose triglyceride lipase) along with its coactivator CGI-58 (Comparative Gene Identification-58) and inhibitor G0S2 (G0/G1 Switch Gene 2). Our studies conducted during the previous finding period 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. The objective of this application is to further define the role of G0S2 in hepatic lipid and energy metabolism, the etiology of obesity-associated insulin resistance, and the development of hepatic steatosis and steatohepatitis. The hypothesis of the proposed studies is that G0S2 is a dual-function protein acting at the TG-lipid droplet (LD) surface as both a lipolytic inhibitor anda lysophosphatidic acid acyltransferase (LPAAT). While both functions contribute to hepatic steatosis during fasting and high fat feeding, G0S2's role as a LPAAT promotes DG synthesis in the liver and is responsible for its detrimental effect in mice with diet-induced obesity (DIO). Th 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 determine the physiologic relevance of G0S2 as a dual-function protein in promoting hepatic TG accumulation; 2) to test the hypothesis that hepatic G0S2 is crucial for survival during extended fasting but detrimental in DIO-associated steatosis; and 3) to determine the mechanisms underlying G0S2 protein degradation and the functional impact of alterations in G0S2 protein stability. 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 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. 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.
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