{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T02:23:59Z","timestamp":1783736639183,"version":"3.55.0"},"reference-count":35,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T00:00:00Z","timestamp":1744675200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health problem and the discovery of drugs is challenging. In this study, we aimed to investigate the effects of intestinal activation of the liver X receptor (LXR)\u03b1 on MASH. Methods: An intestinal-specific LXR\u03b1 activation model in mice was established and subjected to MASH development by combining a Western diet and carbon tetrachloride. Lipid metabolism, reverse cholesterol transport (RCT), steatosis, inflammation, and fibrosis were evaluated. In vitro models of steatosis and fibrosis were used to explore the role of scavenger receptor class B type 1 (SRB1). Results: We found that the intestinal activation of LXR\u03b1 improved several MASLD features, including levels of triglycerides, RCT, steatosis, systemic and hepatic inflammatory profiles, and liver fibrosis. These effects were associated with increased high-density lipoprotein (HDL) levels and hepatic SRB1 expression. In vitro depletion of SRB1 hampered the beneficial effects of HDL on steatosis and fibrogenesis in liver cells by altering the activation of both peroxisome proliferator-activated receptors \u03b3 and small mothers against decapentaplegic homolog protein (SMAD)2\/3 proteins. Conclusions: Our findings showed that the intestinal activation of LXR\u03b1 and a parallel induction of hepatic SRB1 are protective against inflammation, steatosis, and advanced liver fibrosis in MASLD.<\/jats:p>","DOI":"10.3390\/nu17081349","type":"journal-article","created":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T06:50:27Z","timestamp":1744699827000},"page":"1349","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Intestinal Activation of LXR\u03b1 Counteracts Metabolic-Associated Steatohepatitis Features in Mice"],"prefix":"10.3390","volume":"17","author":[{"given":"Gessica","family":"Lioci","sequence":"first","affiliation":[{"name":"Liver Injury and Transplant Unit, Polytechnic University of Marche, 60121 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Gurrado","sequence":"additional","affiliation":[{"name":"Liver Injury and Transplant Unit, Polytechnic University of Marche, 60121 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Panera","sequence":"additional","affiliation":[{"name":"Research Unit of Genetics of Complex Phenotypes, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marzia","family":"Bianchi","sequence":"additional","affiliation":[{"name":"Research Unit of Genetics of Complex Phenotypes, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5898-9518","authenticated-orcid":false,"given":"Cristiano","family":"De Stefanis","sequence":"additional","affiliation":[{"name":"Core Facilities, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"D\u2019Oria","sequence":"additional","affiliation":[{"name":"Core Facilities, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3297-1592","authenticated-orcid":false,"given":"Nicol\u00f2","family":"Cicolani","sequence":"additional","affiliation":[{"name":"Core Facilities, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6577-5892","authenticated-orcid":false,"given":"Silvano","family":"Santini","sequence":"additional","affiliation":[{"name":"Department of Life, Health and Environmental Sciences-MESVA, School of Emergency-Urgency Medicine, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Schiad\u00e0","sequence":"additional","affiliation":[{"name":"Liver Injury and Transplant Unit, Polytechnic University of Marche, 60121 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7241-6329","authenticated-orcid":false,"given":"Anna","family":"Alisi","sequence":"additional","affiliation":[{"name":"Research Unit of Genetics of Complex Phenotypes, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Svegliati-Baroni","sequence":"additional","affiliation":[{"name":"Liver Injury and Transplant Unit, Polytechnic University of Marche, 60121 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1097\/HEP.0000000000000004","article-title":"The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): A systematic review","volume":"77","author":"Younossi","year":"2023","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/j.jhep.2018.05.036","article-title":"Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016\u20132030","volume":"69","author":"Estes","year":"2018","journal-title":"J. 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