{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T16:33:22Z","timestamp":1791909202750,"version":"4.3.4"},"reference-count":28,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2018,5,21]],"date-time":"2018-05-21T00:00:00Z","timestamp":1526860800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2018,5,21]],"date-time":"2018-05-21T00:00:00Z","timestamp":1526860800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2018,8]]},"abstract":"<jats:p>Alcoholic liver disease (ALD) is characterized by lipid accumulation and liver injury. However, how chronic alcohol consumption causes hepatic lipid accumulation remains elusive. The present study demonstrates that activation of the mechanistic target of rapamycin complex 1 (mTORC1) plays a causal role in alcoholic steatosis, inflammation, and liver injury. Chronic\u2010plus\u2010binge ethanol feeding led to hyperactivation of mTORC1, as evidenced by increased phosphorylation of mTOR and its downstream kinase S6 kinase 1 (S6K1) in hepatocytes. Aberrant activation of mTORC1 was likely attributed to the defects of the DEP domain\u2010containing mTOR\u2010interacting protein (DEPTOR) and the nicotinamide adenine dinucleotide\u2013dependent deacetylase sirtuin 1 (SIRT1) in the liver of chronic\u2010plus\u2010binge ethanol\u2010fed mice and in the liver of patients with ALD. Conversely, adenoviral overexpression of hepatic DEPTOR suppressed mTORC1 signaling and ameliorated alcoholic hepatosteatosis, inflammation, and acute\u2010on\u2010chronic liver injury. Mechanistically, the lipid\u2010lowering effect of hepatic DEPTOR was attributable to decreased proteolytic processing, nuclear translocation, and transcriptional activity of the lipogenic transcription factor sterol regulatory element\u2010binding protein\u20101 (SREBP\u20101). DEPTOR\u2010dependent inhibition of mTORC1 also attenuated alcohol\u2010induced cytoplasmic accumulation of the lipogenic regulator lipin 1 and prevented alcohol\u2010mediated inhibition of fatty acid oxidation. Pharmacological intervention with rapamycin alleviated the ability of alcohol to up\u2010regulate lipogenesis, to down\u2010regulate fatty acid oxidation, and to induce steatogenic phenotypes. Chronic\u2010plus\u2010binge ethanol feeding led to activation of SREBP\u20101 and lipin 1 through S6K1\u2010dependent and independent mechanisms. Furthermore, hepatocyte\u2010specific deletion of SIRT1 disrupted DEPTOR function, enhanced mTORC1 activity, and exacerbated alcoholic fatty liver, inflammation, and liver injury in mice. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: The dysregulation of SIRT1\u2013DEPTOR\u2013mTORC1 signaling is a critical determinant of ALD pathology; targeting SIRT1 and DEPTOR and selectively inhibiting mTORC1\u2013S6K1 signaling may have therapeutic potential for treating ALD in humans. (H<jats:sc>epatology<\/jats:sc> 2018).<\/jats:p>","DOI":"10.1002\/hep.29849","type":"journal-article","created":{"date-parts":[[2018,2,21]],"date-time":"2018-02-21T18:22:43Z","timestamp":1519237363000},"page":"496-514","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":112,"title":["DEP domain\u2013containing mTOR\u2013interacting protein suppresses lipogenesis and ameliorates hepatic steatosis and acute\u2010on\u2010chronic liver injury in alcoholic liver disease"],"prefix":"10.1097","volume":"68","author":[{"given":"Hanqing","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine,University of Texas Health San Antonio,San Antonio,TX"},{"name":"Barshop Institute for Longevity and Aging Studies, Center for Healthy Aging,University of Texas Health San Antonio,San 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