{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T12:29:10Z","timestamp":1785932950864,"version":"3.56.0"},"reference-count":17,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2018,1,10]],"date-time":"2018-01-10T00:00:00Z","timestamp":1515542400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan","award":["15K09031"],"award-info":[{"award-number":["15K09031"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatology Research"],"published-print":{"date-parts":[[2018,4]]},"abstract":"<jats:sec><jats:title>Aim<\/jats:title><jats:p>Liver fibrosis is a life\u2010threatening disorder for which no approved therapy is available. Recently, we reported that mouse hepatic stellate cell (HSC) activation increased free cholesterol (FC) accumulation, partly by enhancing signaling through sterol regulatory element\u2010binding protein 2 (SREBP2) and microRNA\u201033a (miR\u201033a), which resulted in HSC sensitization to transforming growth factor\u2010\u03b2 (TGF\u03b2)\u2010induced activation in a \u201cvicious cycle\u201d of liver fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Human HSCs were isolated from surgical liver specimens from control patients and patients with liver fibrosis. C57BL\/6 mice were treated with carbon tetrachloride for 4\u00a0weeks and concurrently given SREBP2\u2010siRNA\u2010 or anti\u2010miR\u201033a\u2010bearing vitamin A\u2010coupled liposomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In human activated HSCs obtained from patients with liver fibrosis, FC accumulation was enhanced independently of serum cholesterol levels through increased signaling by both SREBP2 and miR\u201033a. This increased FC accumulation enhanced Toll\u2010like receptor 4 (TLR4) protein levels and lowered the TGF\u03b2\u2010pseudoreceptor Bambi (bone morphogenetic protein and activin membrane\u2010bound inhibitor) mRNA levels in HSCs. Notably, in a mouse liver fibrosis model, reduction of FC accumulation, specifically in activated HSCs by suppression of SREBP2 or miR\u201033a expression using SREBP2\u2010siRNA\u2010 or anti\u2010miR\u201033a\u2010bearing vitamin A\u2010coupled liposomes, downregulated TLR4 signaling, increased Bambi expression, and consequently ameliorated liver fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results suggest that FC accumulation in HSCs, as an intracellular mediator promoting HSC activation, contributes to a vicious cycle of HSC activation in human and mouse liver fibrosis independent of serum cholesterol levels. Targeting FC accumulation\u2010related molecules in HSCs through a vitamin A\u2010coupled liposomal system represents a favorable therapeutic strategy for liver fibrosis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/hepr.13040","type":"journal-article","created":{"date-parts":[[2017,12,16]],"date-time":"2017-12-16T10:53:34Z","timestamp":1513421614000},"page":"397-407","source":"Crossref","is-referenced-by-count":34,"title":["Vitamin A\u2010coupled liposome system targeting free cholesterol accumulation in hepatic stellate cells offers a beneficial therapeutic strategy for liver fibrosis"],"prefix":"10.1111","volume":"48","author":[{"given":"Hirotaka","family":"Furuhashi","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine National Defense Medical College  Tokorozawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kengo","family":"Tomita","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine National Defense Medical College  Tokorozawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiaki","family":"Teratani","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine Keio University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motonori","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine National Defense Medical College  Tokorozawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Nishikawa","sequence":"additional","affiliation":[{"name":"Department of Surgery National Defense Medical College  Tokorozawa Saitama 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