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Vitamin A‐coupled liposome system targeting free cholesterol accumulation in hepatic stellate cells offers a beneficial therapeutic strategy for liver fibrosis
Author(s) -
Furuhashi Hirotaka,
Tomita Kengo,
Teratani Toshiaki,
Shimizu Motonori,
Nishikawa Makoto,
Higashiyama Masaaki,
Takajo Takeshi,
Shirakabe Kazuhiko,
Maruta Koji,
Okada Yoshikiyo,
Kurihara Chie,
Watanabe Chikako,
Komoto Shunsuke,
Aosasa Suefumi,
Nagao Shigeaki,
Yamamoto Junji,
Miura Soichiro,
Hokari Ryota
Publication year - 2018
Publication title -
hepatology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.123
H-Index - 75
eISSN - 1872-034X
pISSN - 1386-6346
DOI - 10.1111/hepr.13040
Subject(s) - hepatic stellate cell , hepatic fibrosis , endocrinology , medicine , fibrosis , biology , cancer research , chemistry , microbiology and biotechnology
Aim Liver fibrosis is a life‐threatening 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‐binding protein 2 (SREBP2) and microRNA‐33a (miR‐33a), which resulted in HSC sensitization to transforming growth factor‐β (TGFβ)‐induced activation in a “vicious cycle” of liver fibrosis. Methods 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 weeks and concurrently given SREBP2‐siRNA‐ or anti‐miR‐33a‐bearing vitamin A‐coupled liposomes. Results 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‐33a. This increased FC accumulation enhanced Toll‐like receptor 4 (TLR4) protein levels and lowered the TGFβ‐pseudoreceptor Bambi (bone morphogenetic protein and activin membrane‐bound 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‐33a expression using SREBP2‐siRNA‐ or anti‐miR‐33a‐bearing vitamin A‐coupled liposomes, downregulated TLR4 signaling, increased Bambi expression, and consequently ameliorated liver fibrosis. Conclusions 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‐related molecules in HSCs through a vitamin A‐coupled liposomal system represents a favorable therapeutic strategy for liver fibrosis.