{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T04:25:29Z","timestamp":1783571129295,"version":"3.55.0"},"reference-count":49,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,7,27]],"date-time":"2023-07-27T00:00:00Z","timestamp":1690416000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000027","name":"NIAAA","doi-asserted-by":"publisher","award":["R21 AA027637"],"award-info":[{"award-number":["R21 AA027637"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"NIAAA","doi-asserted-by":"publisher","award":["5SC2GM127206-0"],"award-info":[{"award-number":["5SC2GM127206-0"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"NIGMS","doi-asserted-by":"publisher","award":["R21 AA027637"],"award-info":[{"award-number":["R21 AA027637"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"NIGMS","doi-asserted-by":"publisher","award":["5SC2GM127206-0"],"award-info":[{"award-number":["5SC2GM127206-0"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In alcohol-associated liver disease (ALD), hepatic reductions in vitamin A and perturbations in vitamin A metabolism are common. However, the roles that the vitamin A receptors, termed retinoic acid receptors (RARs), may have in preventing the pathophysiology of ALD remains unclear. Our prior data indicate that a RAR\u03b2 agonist limits the pathology of alcohol-related liver disease. Thus, we generated liver-specific AlbCre\u2013RAR\u03b2 knockout (BKO) mice and compared them to wild type (WT) mice in an early ALD model. Both strains showed similar blood ethanol concentrations and ETOH-metabolizing enzymes. However, the livers of pair-fed-BKO and ETOH-BKO mice developed higher levels of steatosis and triglycerides than pair-fed-WT and ETOH-WT mice. The increased hepatic steatosis observed in the pair-fed-BKO and ETOH-BKO mice was associated with higher lipid synthesis\/trafficking transcripts and lower beta-oxidation transcripts. ETOH-BKO mice also exhibited a higher integrated stress response (ISR) signature, including higher transcript and protein levels of ATF4 and its target, 4-EBP1. In human hepatocytes (HepG2) that lack RAR\u03b2 (RAR\u03b2-KO), ETOH treatments resulted in greater reactive oxygen species compared to their parental cells. Notably, even without ETOH, ATF4 and 4-EBP1 protein levels were higher in the RAR\u03b2-KO cells than in their parental cells. These 4-EBP1 increases were greatly attenuated in cultured ATF4-deficient and RAR\u03b2\/ATF4-deficient HepG2, suggesting that RAR\u03b2 is a crucial negative regulator of 4-EBP1 through ATF4 in cultured hepatocytes. Here, we identify RAR\u03b2 as a negative regulator of lipid metabolism and cellular stress in ALD.<\/jats:p>","DOI":"10.3390\/ijms241512035","type":"journal-article","created":{"date-parts":[[2023,7,28]],"date-time":"2023-07-28T01:51:47Z","timestamp":1690509107000},"page":"12035","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Retinoic Acid Receptor \u03b2 Loss in Hepatocytes Increases Steatosis and Elevates the Integrated Stress Response in Alcohol-Associated Liver Disease"],"prefix":"10.3390","volume":"24","author":[{"given":"Marta","family":"Melis","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven E.","family":"Trasino","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA"},{"name":"Nutrition Program, Hunter College, City University of New York, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9610-6608","authenticated-orcid":false,"given":"Xiao-Han","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Rappa","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Genomics Resources Core Facility, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihui","family":"Qin","sequence":"additional","affiliation":[{"name":"Division of Anatomic Pathology, New York Presbyterian Hospital, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3115-4777","authenticated-orcid":false,"given":"Lorraine J.","family":"Gudas","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/s41572-018-0014-7","article-title":"Alcoholic liver disease","volume":"4","author":"Seitz","year":"2018","journal-title":"Nat. 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