The microRNA Control of Alcoholic Liver Injury and Hepatic Lipid Metabolism

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ABSTRACT The prevalence of alcoholic liver disease is rising with concomitant increase in morbidity and mortality rates worldwide. Accumulation of lipid droplets in hepatocytes is the fundamental hallmark of steatosis and represents the initial manifestation of alcoholic fatty liver (AFL), which can progress to severe liver injury leading to cirrhosis and hepatocellular carcinoma. Despite the increasing prevalence of AFL, no effective therapies or established medical treatments exist. microRNAs are small non coding RNAs of 22 nucleotides in length which have diverse roles in various cancers and other liver-related diseases. miR-200c has been implicated in the development of non-alcoholic liver disease, however no studies to date have investigated the role of miR-200c on AFL. Our central hypothesis of the proposed study is that miR-200c is a critical regulator of alcohol-induced liver injury, inflammation and lipid accumulation. We aim to: (1) Identify the molecular mechanisms by which miR-200c mediates AFL; (2) Investigate the pathways associated with miR-200c-mediated alterations in hepatic metabolism during alcohol exposure; (3) Elucidate that the regulatory function of miR-200c in alcohol-induced inflammation. We will take advantage of genetic, molecular and pharmacological approaches to address the role of miR-200c on AFL. To address our questions, we will utilize a comprehensive experimental approach that integrates the use of in vitro cell culture model and in vivo mouse models complementing each other, allowing for a highly targeted pathophysiological and molecular approach. The proposed studies are well equipped to delineate the underlying mechanisms by which miR-200c regulates hepatic lipid accumulation and inflammation during alcohol exposure.