Alcoholic steatohepatitis is characterized by hepatic steatosis, inflammatory infiltrate, and progression to liver fibrosis. It is one of the most prevalnt forms of chronic liver disease which may progress to fibrosis, cirrhosis, hepatocellular cancer. The underlying mechanisms by which ethanol consumption leads to steatosis/steatohepatitis are multiple, complex and incompletely understood. This grant is currently in its 10th year and has supported 29 original papers and 6 reviews. During the 10 year grant period, we have discovered that chronic ethanol consumption causes the development and maintenance of fatty liver in mice by affecting several important liver transcriptional regulators involved in controls pathways of lipid metabolism;namely, sterol regulatory element binding protein 1 (SREBP-1), PPAR-gamma co-activator-alpha (PGC-1-alpha) and AMP-activated kinase (AMPK). More importantly, sirtuin 1 (SIRT1), an NAD+-dependent class III protein deacetylase, has been identified as a vital bridging molecule that links ethanol metabolism with downstream effects (including activation of aforementioned transcriptional regulators and the expression of genes that ultimately promote lipid accumulation and inflammation). In the past funding cycle, our group has further investigated the underlying mechanisms of ethanol-mediated hepatic SIRT1 inhibition by identifying a new hepatic target of ethanol action, microRNA-217 (miR-217). We found that ethanol drastically and specifically up-regulates hepatic miR-217, and inhibits SIRT1, and ultimately causes excessive accumulation of lipid and inflammation. Therefore, this current proposal examines a novel and exciting hypothesis that hepatic miR-217 plays a vital role in the development of alcoholic steatohepatitis. The three Specific Aims of the proposal are to: (1) Investigate the role of miR-217 in the development of alcoholic steatohepatitis in mice. (2) Investigate the underlying mechanisms by which ethanol up-regulates miR-217 and causes steatosis in cultured hepatocytes and in mouse livers. (3) Investigate the underlying mechanisms by which ethanol up- regulates miR-217 and causes inflammation in cultured Kupffer cells and in mouse livers. We will utilize state- of-the-art molecular, cellular, and biochemical approaches with cell culture and genetically or adenoviral modified mouse models to dissect the signaling events mediating the action of ethanol on hepatic miR-217- SIRT1 axis. The long term goal of this research project is to translate our findings from the laboratory to bedside to better understand the mechanisms underlying alcoholic steatosis/steatohepatitis, and to ultimately discover novel targets and therapeutic approaches for preventing and treating human alcoholic steatosis/steatohepatitis.
Sirtuin 1 (SIRT1), an NAD+-dependent class III protein deacetylase, is a master regulator of the transcriptional networks that control hepatic lipid metabolism and inflammation. This renewal application will study the molecular mechanisms by which ethanol inhibits SIRT1 and impairs its hepatic signaling. This study will increase our knowledge of the pathogenesis and therapeutics for treatment of human alcoholic steatosis/ steatohepatitis.
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