mTORC1 activation and alcoholic liver injuryKey words: alcohol fatty liver, mTORC1, DEPTOR, ER stress, and SREBP-1Alcoholism is a leading cause of liver disease in Western societies. Hepatic steatosis (fatty liver) is an earlyand reversible stage of alcoholic liver disease. However, unchecked hepatic steatosis can develop intoirreversible steatohepatitis, fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. Alcoholic fatty liverdisease (AFLD) is attributed to the activation of endoplasmic reticulum (ER) stress signaling. However, themolecular mechanisms underlying hepatic ER stress in AFLD are not fully understood. Although greatprogress has been made in the identification of mammalian target of rapamycin complex 1 (mTORC1) pathwaycomponents, relatively little is known about the in vivo role of the mTORC1 pathway in alcoholic liverpathophysiology. Our recent studies demonstrate that hepatic inhibition of mTORC1 by the NAD-dependentdeacetylase SIRT1 suppresses hepatic ER stress, downregulates lipogenesis, and thereby ameliorates hepaticsteatosis in diabetic mice. Exciting preliminary data show that hepatic mTORC1 is activated in chronic bingealcohol-fed mice, which is accompanied by induction of ER stress, activation of lipogenesis, and hepaticsteatosis. Importantly, new studies suggest that consistent with mTORC1 activation, hepatic levels ofDEPTOR, a newly identified endogenous inhibitor of mTORC1, are reduced in alcohol-fed mice. To betterunderstand the pathogenesis of alcoholic liver disease and develop alternative therapeutic strategies for thedisease, our CENTRAL HYPOTHESIS is that mTORC1 plays a key role in alcoholic fatty liver disease bypromoting hepatic ER stress and stimulating lipogenesis.
Two specific aims are proposed: 1) Tocharacterize the functional and mechanistic role of mTORC1 in alcohol-induced ER stress and lipogenesis inhepatocytes; 2) To determine whether mTORC1 inhibition ameliorates hepatic steatosis and ER stress in micewith alcoholic fatty liver. In response to the NIAAA program (PA-10-094) entitled ?stress pathways in alcoholinduced organ injury and protection?, the proposed studies will determine whether chronic alcohol exposureresults in mTORC1 activation via mTORC1 components such as DEPTOR, TSC1/2 or Raptor and therebyaccelerates the development of hepatic steatosis and ER stress. In vitro cell-based mechanistic studies as wellas in vivo pharmacologic and genetic approaches of manipulating hepatic mTORC1 activity will be utilized.Innovative aspects of these proposed studies include: (1) new insight into mTORC1 as a novel regulator ofalcohol-induced ER stress pathways and fatty liver; (2) the novel concept that DEPTOR-dependent inhibitionof mTORC1 ameliorates alcoholic fatty liver and liver injury by relieving ER stress and inhibiting lipogenesis;(3) DEPTOR/mTORC1 as new targets for the therapeutic interventions of AFLD and ER stress-related liverdiseases such as cancer. Our long-term objective is to elucidate the pathological mechanisms of AFLD, toidentify novel molecular targets for intervention at this early and reversible stage of alcoholic liver disease, andto develop a potential marker of AFLD to aid early diagnosis and prognosis.
mTORC1 activation and alcoholic liver injuryExcessive alcohol consumption is the third leading cause of preventable death in the US. However; thepathological mechanisms of alcoholic fatty liver disease are not largely understood. This proposal will identifyactivation of a protein kinase; mTORC1; as a novel mechanism to explain the effects of alcohol excess onstress signaling pathways in the liver. Therefore; the proposed studies will help illuminate how chronic alcoholconsumption results in liver injury and will provide novel insight into newly effective treatment strategies toalleviate alcoholic liver disease.
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