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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21AA021181-03
Application #
9281522
Study Section
Biomedical Research Review Subcommittee (AA-1)
Program Officer
Radaeva, Svetlana
Project Start
2013-09-15
Project End
2017-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
3
Fiscal Year
2014
Total Cost
$175,660
Indirect Cost
$60,473
Name
University of Texas Health Science Center
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Chen, Hanqing; Shen, Feng; Sherban, Alex et al. (2018) DEP domain-containing mTOR-interacting protein suppresses lipogenesis and ameliorates hepatic steatosis and acute-on-chronic liver injury in alcoholic liver disease. Hepatology 68:496-514
Ramirez, Teresa; Li, Yong-Mei; Yin, Shi et al. (2017) Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression. J Hepatol 66:601-609
Shen, Qiwei; Yang, Yeping; Liu, Wenjuan et al. (2017) Organ-specific alterations in circadian genes by vertical sleeve gastrectomy in an obese diabetic mouse model. Sci Bull (Beijing) 62:467-469
Li, Xiaoyu; Kover, Karen L; Heruth, Daniel P et al. (2017) Thioredoxin-interacting protein promotes high-glucose-induced macrovascular endothelial dysfunction. Biochem Biophys Res Commun 493:291-297
Luo, Ting; Nocon, Allison; Fry, Jessica et al. (2016) AMPK Activation by Metformin Suppresses Abnormal Extracellular Matrix Remodeling in Adipose Tissue and Ameliorates Insulin Resistance in Obesity. Diabetes 65:2295-310
Han, Jingyan; Weisbrod, Robert M; Shao, Di et al. (2016) The redox mechanism for vascular barrier dysfunction associated with metabolic disorders: Glutathionylation of Rac1 in endothelial cells. Redox Biol 9:306-319
Gong, Qi; Hu, Zhimin; Zhang, Feifei et al. (2016) Fibroblast growth factor 21 improves hepatic insulin sensitivity by inhibiting mammalian target of rapamycin complex 1 in mice. Hepatology 64:425-38
Li, Xiaoyu; Kover, Karen L; Heruth, Daniel P et al. (2015) New Insight Into Metformin Action: Regulation of ChREBP and FOXO1 Activities in Endothelial Cells. Mol Endocrinol 29:1184-94
Li, Yu; Wong, Kimberly; Giles, Amber et al. (2014) Hepatic SIRT1 attenuates hepatic steatosis and controls energy balance in mice by inducing fibroblast growth factor 21. Gastroenterology 146:539-49.e7
Li, Yu; Xu, Shanqin; Mihaylova, Maria M et al. (2011) AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab 13:376-388

Showing the most recent 10 out of 11 publications