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Liver fibrosis is the strongest prognostic factor for clinical outcomes, liver\u2010related mortality and liver transplantation. Currently, no single therapy or medication for NASH has been approved by the U.S. Food and Drug Administration (FDA). Oxy210, an oxysterol derivative, displays the unique property of antagonizing both Hedgehog (Hh) and transforming growth factor\u2010beta (TGF\u2010\u03b2) signalling in primary human hepatic stellate cells (HSC). We hypothesized that inhibition of both Hh and TGF\u2010\u03b2 signalling by Oxy210 could reduce hepatic fibrosis in NASH. In this study, we examined the therapeutic potential of Oxy210 on NASH in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We examined the effect of Oxy210 treatment on Hh and TGF\u2010\u03b2 pathways in HSC. The efficacy of Oxy210 on liver fibrosis was tested in a \u2018humanized\u2019 hyperlipidemic mouse model of NASH that has high relevance to human pathology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Approach and Results<\/jats:title><jats:p>We show that Oxy210 inhibits both Hh and TGF\u2010\u03b2 pathways in human HSC and attenuates baseline and TGF\u2010\u03b2\u2010induced expression of pro\u2010fibrotic genes <jats:italic>in vitro<\/jats:italic>. Oral delivery of Oxy210 in food resulted in significant liver exposure and significantly reduced hepatic fibrosis in mice over the course of the 16\u2010week study with no apparent safety issues. Additionally, we observed several benefits related to NASH phenotype: (a) reduced plasma pro\u2010inflammatory cytokine and the corresponding hepatic gene expression; (b) reduced pro\u2010fibrotic cytokine and inflammasome gene expression in the liver; (c) reduced apoptosis in the liver; (d) reduced hepatic unesterified cholesterol accumulation; and (e) reduced plasma total and unesterified cholesterol levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Oxy210 effectively ameliorated hepatic fibrosis and inflammation and improved hypercholesterolemia in mice. Our findings suggest that Oxy210 and related analogues are a new class of drug candidates that may serve as potential therapeutics candidates for NASH.<\/jats:p><\/jats:sec>","DOI":"10.1002\/edm2.296","type":"journal-article","created":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T18:13:26Z","timestamp":1630433606000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Oxy210, a novel inhibitor of hedgehog and TGF\u2010\u03b2 signalling, ameliorates hepatic fibrosis and hypercholesterolemia in mice"],"prefix":"10.1002","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3540-3013","authenticated-orcid":false,"given":"Simon T.","family":"Hui","sequence":"first","affiliation":[{"name":"Department of Medicine Division of Cardiology David Geffen School of Medicine University of California Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Wang","sequence":"additional","affiliation":[{"name":"MAX BioPharma, Inc Santa Monica California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Stappenbeck","sequence":"additional","affiliation":[{"name":"MAX BioPharma, Inc Santa Monica California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel W.","family":"French","sequence":"additional","affiliation":[{"name":"Department of Pathology &amp; Laboratory Medicine David Geffen School of Medicine University of California Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara E.","family":"Magyar","sequence":"additional","affiliation":[{"name":"Department of Pathology &amp; Laboratory Medicine David Geffen School of Medicine University of California Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farhad","family":"Parhami","sequence":"additional","affiliation":[{"name":"MAX BioPharma, Inc Santa Monica California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aldons J.","family":"Lusis","sequence":"additional","affiliation":[{"name":"Department of Medicine Division of Cardiology David Geffen School of Medicine University of California Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,31]]},"reference":[{"issue":"389","key":"e_1_2_9_2_1","first-page":"e310","article-title":"liver fibrosis, but no other histologic features, is associated with long\u2010term outcomes of patients with nonalcoholic fatty liver disease","volume":"149","author":"Angulo P","year":"2015","journal-title":"Gastroenterology"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005711"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v25.i33.4904"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00079.2013"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2016.1257453"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-011-1246-y"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M611741200"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27368"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aam7928"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0082190"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.07.027"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-011110-130246"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0070599"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30113"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.05607"},{"key":"e_1_2_9_17_1","first-page":"2683","article-title":"Morphological and functional characterization of non\u2010alcoholic fatty liver disease induced by a methionine\u2010choline\u2010deficient diet in C57BL\/6 mice","volume":"6","author":"Itagaki H","year":"2013","journal-title":"Int J Clin Exp Pathol"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1177\/0884533611419668"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0054499"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.10.017"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0127991"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1161\/hh2201.099415"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3823"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.3976"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2213"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdrb.21093"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.2337\/db06-S002"},{"key":"e_1_2_9_28_1","first-page":"42","article-title":"Non\u2010alcoholic fatty liver disease, an overview","volume":"18","author":"Nd AM","year":"2019","journal-title":"Integr Med"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cct.2019.105889"},{"issue":"372","key":"e_1_2_9_30_1","first-page":"2010","article-title":"A position statement on NAFLD\/NASH based on the EASL 2009 special conference","volume":"53","author":"Ratziu V","year":"2010","journal-title":"J Hepatol"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells8101297"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.02.039"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.25668"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells8050509"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2016.00047"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)33041-7"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2020.05.064"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1590\/1414-431X20133058"}],"container-title":["Endocrinology, Diabetes &amp; 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