{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:13:09Z","timestamp":1788437589669,"version":"build-2803163510"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2022,4,16]],"date-time":"2022-04-16T00:00:00Z","timestamp":1650067200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2022,4,16]],"date-time":"2022-04-16T00:00:00Z","timestamp":1650067200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>NASH is associated with high levels of cholesterol and triglyceride (TG) in the liver; however, there is still no approved pharmacological therapy. Synthesis of cholesterol and TG is controlled by sterol regulatory element\u2010binding protein (SREBP), which is found to be abnormally activated in NASH patients. We aim to discover small molecules for treating NASH by inhibiting the SREBP pathway.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>Here, we identify a potent SREBP inhibitor, 25\u2010hydroxylanosterol (25\u2010HL). 25\u2010HL binds to insulin\u2010induced gene (INSIG) proteins, stimulates the interaction between INSIG and SCAP, and retains them in the endoplasmic reticulum, thereby suppressing SREBP activation and inhibiting lipogenesis. In NASH mouse models, 25\u2010HL lowers levels of cholesterol and TG in serum and the liver, enhances energy expenditure to prevent obesity, and improves insulin sensitivity. 25\u2010HL dramatically ameliorates hepatic steatosis, inflammation, ballooning, and fibrosis through down\u2010regulating the expression of lipogenic genes. Furthermore, 25\u2010HL exhibits both prophylactic and therapeutic efficacies of alleviating NASH and atherosclerosis in amylin liver NASH model diet\u2010treated <jats:italic toggle=\"yes\">Ldlr\u2212\/\u2212\n                                 <\/jats:italic> mice, and reduces the formation of cholesterol crystals and associated crown\u2010like structures of Kupffer cells. Notably, 25\u2010HL lowers lipid contents in serum and the liver to a greater extent than lovastatin or obeticholic acid. 25\u2010HL shows a good safety and pharmacokinetics profile.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>This study provides the proof of concept that inhibiting SREBP activation by targeting INSIG to lower lipids could be a promising strategy for treating NASH. It suggests the translational potential of 25\u2010HL in human NASH and demonstrates the critical role of SREBP\u2010controlled lipogenesis in the progression of NASH by pharmacological inhibition.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32381","type":"journal-article","created":{"date-parts":[[2022,2,1]],"date-time":"2022-02-01T02:49:47Z","timestamp":1643683787000},"page":"1466-1481","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":52,"title":["Discovery of an insulin\u2010induced gene binding compound that ameliorates nonalcoholic steatohepatitis by inhibiting sterol regulatory element\u2010binding protein\u2013mediated lipogenesis"],"prefix":"10.1097","volume":"76","author":[{"given":"Shi\u2010You","family":"Jiang","sequence":"first","affiliation":[{"name":"12390,Hubei Key Laboratory of Cell Homeostasis,College of Life Sciences,Wuhan University,Wuhan,China"},{"name":"387433,Gene Editing Center,School of 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