{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:08:27Z","timestamp":1791518907982,"version":"4.3.4"},"reference-count":31,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T00:00:00Z","timestamp":1634083200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["R01AA018844, R01AA020212"],"award-info":[{"award-number":["R01AA018844, R01AA020212"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Alcohol-related liver disease (ALD) is characterized by accumulation of hepatic free fatty acids (FFAs) and liver injury. The present study aimed to investigate if mechanistic target of rapamycin complex 1 (mTORC1) plays a role in FFA-induced organelle dysfunction, thereby contributing to the development of ALD. Cell studies were conducted to define the causal role and underlying mechanism of FFA-activated mTORC1 signaling in hepatocellular cell injury. C57BL\/6J wild-type mice were subjected to chronic alcohol feeding with or without rapamycin to inhibit mTORC1 activation. We revealed that palmitic acid (PA)-induced ER stress and suppression of LAMP2 and autophagy flux were mTORC1-dependent as rapamycin reversed such deleterious effects. C\/EBP homologous protein (CHOP) was downstream of ATF4 which partially modulated LAMP2. Supplementation with rapamycin to alcohol-fed mice attenuated mTORC1 activation and ER stress, restored LAMP2 protein, and improved autophagy, leading to amelioration of alcohol-induced liver injury. Induction of mTORC1 signaling and CHOP were also detected in the liver of patients with severe alcoholic hepatitis. This study demonstrates that hepatic FFAs play a crucial role in the pathogenesis of ALD by activating mTORC1 signaling, thereby inducing ER stress and suppressing LAMP2-autophagy flux pathway, which represents an important mechanism of FFA-induced hepatocellular injury.<\/jats:p>","DOI":"10.3390\/cells10102730","type":"journal-article","created":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T09:33:02Z","timestamp":1634117582000},"page":"2730","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Activation of mTORC1 by Free Fatty Acids Suppresses LAMP2 and Autophagy Function via ER Stress in Alcohol-Related Liver Disease"],"prefix":"10.3390","volume":"10","author":[{"given":"Wei","family":"Guo","sequence":"first","affiliation":[{"name":"Centers for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhong","sequence":"additional","affiliation":[{"name":"Centers for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA"},{"name":"Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liuyi","family":"Hao","sequence":"additional","affiliation":[{"name":"Centers for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinguo","family":"Sun","sequence":"additional","affiliation":[{"name":"Centers for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanxiang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Centers for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA"},{"name":"Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1053\/j.gastro.2011.09.002","article-title":"Alcoholic Liver Disease: Pathogenesis and New Therapeutic Targets","volume":"141","author":"Gao","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/j.cell.2017.02.004","article-title":"mTOR Signaling in Growth, Metabolism, and Disease","volume":"168","author":"Saxton","year":"2017","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.cell.2012.03.017","article-title":"mTOR signaling in growth control and disease","volume":"149","author":"Laplante","year":"2012","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1002\/hep.29849","article-title":"DEP domain-containing mTOR-interacting protein suppresses lipogenesis and ameliorates hepatic steatosis and acute-on-chronic liver injury in alcoholic liver disease","volume":"68","author":"Chen","year":"2018","journal-title":"Hepatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/nrm3025","article-title":"mTOR: From growth signal integration to cancer, diabetes and ageing","volume":"12","author":"Zoncu","year":"2011","journal-title":"Nat. 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