Lipin-1, a mammalian phosphatidic acid phosphatase (PAP), has recently emerged as a key regulator involved in various signaling pathways in lipid metabolism via its function as a PAP enzyme in the triglyceride synthesis pathway and in the nucleus as a transcriptional regulator. Prior to the identification of lipin-1 in 2001, ethanol- mediated activation of hepatic PAP activity was shown to be closely associated with the development of liver steatosis in rodents and humans. However, there is little knowledge of the molecular mechanisms and signaling pathways affected by ethanol, which result in altering the gene and protein expression of lipin-1 and its functions in liver. Therefore, the objective of the current proposal is to test the hypothesis that chronic ethanol exposure may significantly impair the functional activity of lipin-1 in the liver. Such impairment may lead to derangement of hepatic lipid metabolism, thereby contributing to increased hepatic lipid synthesis, reduced oxidation, and suppressed VLDL secretion, and ultimately liver steatosis. We will use state-of-the-art molecular, cellular, and biochemical approaches, unique hepatic cell culture and genetically modified mice models to test our hypotheses. The two Specific Aims of the proposal are to: (1) Investigate the role of lipin-1 in the development of alcoholic fatty liver in mice; (2) Identify the mechanisms through which ethanol causes lipin-1 Hyper-acetylation/Hypo-SUMOylation, reduces nuclear localization of Lipin-1 and impairs nuclear Lipin- 1 co-transcriptional activity in cultured hepatic cells and in mice. The studies carried out within these proposed Specific Aims will facilitate the development of nutritional or pharmacological agents to target Lipin-1 and its signaling pathways in treating human AFLD. The proposed studies presented here are also expected to shed light on the molecular mechanisms underlying both AFLD and NAFLD.
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