Vitamin A-coupled liposome system targeting free cholesterol accumulation in hepatic stellate cells offers a beneficial therapeutic strategy for liver fibrosis

Hirotaka Furuhashi, Kengo Tomita, Toshiaki Teratani, Motonori Shimizu, Makoto Nishikawa, Masaaki Higashiyama, Takeshi Takajo, Kazuhiko Shirakabe, Koji Maruta, Yoshikiyo Okada, Chie Kurihara, Chikako Watanabe, Shunsuke Komoto, Suefumi Aosasa, Shigeaki Nagao, Junji Yamamoto, Soichiro Miura, Ryota Hokari

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)397-407
Number of pages11
JournalHepatology Research
Volume48
Issue number5
DOIs
Publication statusPublished - 2018 Apr

Keywords

  • free cholesterol
  • hepatic stellate cell
  • liver fibrosis
  • microRNA-33a
  • sterol regulatory element-binding protein 2
  • vitamin A-coupled liposomal system

ASJC Scopus subject areas

  • Hepatology
  • Infectious Diseases

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