{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T18:06:15Z","timestamp":1790445975757,"version":"4.1.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2022,1,3]],"date-time":"2022-01-03T00:00:00Z","timestamp":1641168000000},"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":[[2022,5]]},"abstract":"<jats:p>The oxysterol receptor liver X receptor (LXR) is a nuclear receptor best known for its function in the regulation of lipid and cholesterol metabolism. LXRs, both the \u03b1 and \u03b2 isoforms, have been suggested as potential therapeutic targets for several cancer types. However, there was a lack of report on whether and how <jats:italic toggle=\"yes\">LXR\u03b1<\/jats:italic> plays a role in the development of hepatocellular carcinoma (HCC). In the current study, we found that systemic activation of <jats:italic toggle=\"yes\">LXR\u03b1<\/jats:italic> in the <jats:italic toggle=\"yes\">VP\u2010LXR\u03b1<\/jats:italic> knock\u2010in (<jats:italic toggle=\"yes\">LXR\u03b1KI<\/jats:italic>) mice or hepatocyte\u2010specific activation of <jats:italic toggle=\"yes\">LXR\u03b1<\/jats:italic> in the <jats:italic toggle=\"yes\">VP\u2010LXR\u03b1<\/jats:italic> transgenic mice sensitized mice to liver tumorigenesis induced by the combined treatment of diethylnitrosamine (DEN) and 3,3',5,5'\u2010tetrachloro\u20101,4\u2010bis (pyridyloxy) benzene (TCPOBOP). Mechanistically, the <jats:italic toggle=\"yes\">LXR\u03b1\u2010<\/jats:italic>responsive up\u2010regulation of interleukin\u20106 (IL\u20106)\/signal transducer and activator of transcription 3 (STAT3) signaling pathway and the complement system, and down\u2010regulation of bile acid metabolism, may have contributed to increased tumorigenesis. Accumulations of secondary bile acids and oxysterols were found in both the serum and liver tissue of <jats:italic toggle=\"yes\">LXR\u03b1<\/jats:italic> activated mice. We also observed an induction of monocytic myeloid\u2013derived suppressor cells accompanied by down\u2010regulation of dendritic cells and cytotoxic T cells in DEN\/TCPOBOP\u2010induced liver tumors, indicating that chronic activation of <jats:italic toggle=\"yes\">LXR\u03b1<\/jats:italic> may have led to the activation of innate immune suppression. The HCC sensitizing effect of <jats:italic toggle=\"yes\">LXR\u03b1<\/jats:italic> activation was also observed in the <jats:italic toggle=\"yes\">c\u2010MYC<\/jats:italic> driven HCC model. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Our results indicated that chronic activation of <jats:italic toggle=\"yes\">LXR\u03b1<\/jats:italic> promotes HCC, at least in part, by promoting innate immune suppressor as a result of accumulation of oxysterols, as well as up\u2010regulation of the IL\u20106\/Janus kinase\/STAT3 signaling and complement pathways.<\/jats:p>","DOI":"10.1002\/hep4.1880","type":"journal-article","created":{"date-parts":[[2022,1,4]],"date-time":"2022-01-04T03:19:26Z","timestamp":1641266366000},"page":"1123-1139","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":15,"title":["Chronic Activation of LXR\u03b1 Sensitizes Mice to Hepatocellular 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