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Desmosterol, which is converted by \u039424\u2010dehydrocholesterol reductase (DHCR24) into cholesterol, is a potent endogenous LXR agonist with anti\u2010inflammatory properties. We aimed to investigate the effects of DHCR24 inhibition on NAFLD\/NASH development. Here, by using APOE*3\u2010Leiden. CETP mice, a well\u2010established translational model that develops diet\u2010induced human\u2010like NAFLD\/NASH characteristics, we report that SH42, a published DHCR24 inhibitor, markedly increases desmosterol levels in liver and plasma, reduces hepatic lipid content and the steatosis score, and decreases plasma fatty acid and cholesteryl ester concentrations. Flow cytometry showed that SH42 decreases liver inflammation by preventing Kupffer cell activation and monocyte infiltration. LXR\u03b1 deficiency completely abolishes these beneficial effects of SH42. Together, the inhibition of DHCR24 by SH42 prevents diet\u2010induced hepatic steatosis and inflammation in a strictly LXR\u03b1\u2010dependent manner without causing hyperlipidemia. Finally, we also showed that SH42 treatment decreased liver collagen content and plasma alanine transaminase levels in an established NAFLD model. In conclusion, we anticipate that pharmacological DHCR24 inhibition may represent a novel therapeutic strategy for treatment of NAFLD\/NASH.<\/jats:p>","DOI":"10.15252\/emmm.202216845","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T04:22:07Z","timestamp":1687753327000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Inhibition of DHCR24 activates LXR\u03b1 to ameliorate hepatic steatosis and inflammation"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3739-4934","authenticated-orcid":false,"given":"Enchen","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0815-1076","authenticated-orcid":false,"given":"Xiaoke","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6066-3031","authenticated-orcid":false,"given":"Hiroyuki","family":"Nakashima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rumei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendrik J P","family":"van der Zande","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1163-2527","authenticated-orcid":false,"given":"Christoph","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0009-8629","authenticated-orcid":false,"given":"Franz","family":"Bracher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3265-3332","authenticated-orcid":false,"given":"Yassene","family":"Mohammed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan Freark","family":"de Boer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Folkert","family":"Kuipers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8856-5799","authenticated-orcid":false,"given":"Bruno","family":"Guigas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher K","family":"Glass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8455-4988","authenticated-orcid":false,"given":"Patrick C N","family":"Rensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1684-1894","authenticated-orcid":false,"given":"Martin","family":"Giera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0327-0458","authenticated-orcid":false,"given":"Yanan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,6,26]]},"reference":[{"key":"BFEMMM202216845_CR1","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1002\/hep.26046","volume":"57","author":"M Aparicio\u2010Vergara","year":"2013","unstructured":"Aparicio\u2010Vergara M, Hommelberg PP, Schreurs M, Gruben N, Stienstra R, Shiri\u2010Sverdlov R, Kloosterhuis NJ, de Bruin A, van de Sluis B, Koonen DP et\u00a0al (2013) Tumor necrosis factor receptor 1 gain\u2010of\u2010function mutation aggravates nonalcoholic fatty liver disease but does not cause insulin resistance in a murine model. 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