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.
Excess alcohol consumption can lead excess fat accumulation in the liver, resulting in the development of alcoholic fatty liver which is the most common cause of liver dysfunction. Currently no effective therapies or established medical treatments exist to reduce the risk of fatty liver disease. Therefore, it is imperative to investigate the contributing factors that may lead to alcoholic fatty liver to help develop novel therapeutic strategies to alleviate the incidence of morbidity caused by chronic alcohol consumption. The proposed studies will investigate the regulatory role of microRNA on alcohol induced fatty liver and identify the molecular basis of this regulation.
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