{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T20:16:18Z","timestamp":1790972178589,"version":"4.1.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","license":[{"start":{"date-parts":[[2022,10,5]],"date-time":"2022-10-05T00:00:00Z","timestamp":1664928000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Nonalcoholic steatohepatitis (NASH) is a rapidly developing pathology around the world, with limited treatment options available. Some farnesoid X receptor (FXR) agonists have been applied in clinical trials for NASH, but side effects such as pruritus and low\u2010density lipoprotein elevation have been reported. Intestinal FXR is recognized as a promising therapeutic target for metabolic diseases. Glycine\u2010\u03b2\u2010muricholic acid (Gly\u2010MCA) is an intestine\u2010specific FXR antagonist previously shown to have favorable metabolic effects on obesity and insulin resistance. Herein, we identify a role for Gly\u2010MCA in the pathogenesis of NASH, and explore the underlying molecular mechanism. Gly\u2010MCA improved lipid accumulation, inflammatory response, and collagen deposition in two different NASH models. Mechanistically, Gly\u2010MCA decreased intestine\u2010derived ceramides by suppressing ceramide synthesis\u2013related genes via decreasing intestinal FXR signaling, leading to lower liver endoplasmic reticulum (ER) stress and proinflammatory cytokine production. The role of bile acid metabolism and adiposity was excluded in the suppression of NASH by Gly\u2010MCA, and a correlation was found between intestine\u2010derived ceramides and NASH severity. This study revealed that Gly\u2010MCA, an intestine\u2010specific FXR antagonist, has beneficial effects on NASH by reducing ceramide levels circulating to liver via lowering intestinal FXR signaling, and ceramide production, followed by decreased liver ER stress and NASH progression. Intestinal FXR is a promising drug target and Gly\u2010MCA a novel agent for the prevention and treatment of NASH.<\/jats:p>","DOI":"10.1002\/hep4.2099","type":"journal-article","created":{"date-parts":[[2022,10,5]],"date-time":"2022-10-05T07:41:43Z","timestamp":1664955703000},"page":"3363-3378","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":27,"title":["Glycine\u2010\u03b2\u2010muricholic acid antagonizes the intestinal farnesoid X receptor\u2013ceramide axis and ameliorates NASH in mice"],"prefix":"10.1097","volume":"6","author":[{"given":"Jie","family":"Jiang","sequence":"first","affiliation":[{"name":"School of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing,China"},{"name":"State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica, Chinese Academy of Sciences,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuandi","family":"Ma","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica, Chinese Academy of Sciences,Shanghai,China"},{"name":"University of Chinese Academy of Sciences,Beijing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yameng","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica, Chinese Academy of Sciences,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dasheng","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine,The Pennsylvania State University,Hershey,Pennsylvania,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxia","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine,The Pennsylvania State University,Hershey,Pennsylvania,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristopher W.","family":"Krausz","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine,The Pennsylvania State University,Hershey,Pennsylvania,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhimant","family":"Desai","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolism, Center for Cancer Research,National Cancer Institute, National Institutes of Health,Bethesda,Maryland,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shantu G.","family":"Amin","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolism, Center for Cancer Research,National Cancer Institute, National Institutes of Health,Bethesda,Maryland,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew 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