Acyl-CoA:cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells

Kengo Tomita, Toshiaki Teratani, Takahiro Suzuki, Motonori Shimizu, Hirokazu Sato, Kazuyuki Narimatsu, Shingo Usui, Hirotaka Furuhashi, Akifumi Kimura, Kiyoshi Nishiyama, Tadashi Maejima, Yoshikiyo Okada, Chie Kurihara, Katsuyoshi Shimamura, Hirotoshi Ebinuma, Hidetsugu Saito, Hirokazu Yokoyama, Chikako Watanabe, Shunsuke Komoto, Shigeaki NagaoKazuo Sugiyama, Suefumi Aosasa, Kazuo Hatsuse, Junji Yamamoto, Toshifumi Hibi, Soichiro Miura, Ryota Hokari, Takanori Kanai

研究成果: Article査読

57 被引用数 (Scopus)

抄録

Background & Aims Acyl-coenzyme A: cholesterol acyltransferase (ACAT) catalyzes the conversion of free cholesterol (FC) to cholesterol ester, which prevents excess accumulation of FC. We recently found that FC accumulation in hepatic stellate cells (HSCs) plays a role in progression of liver fibrosis, but the effect of ACAT1 on liver fibrosis has not been clarified. In this study, we aimed to define the role of ACAT1 in the pathogenesis of liver fibrosis. Methods ACAT1-deficient and wild-type mice, or Toll-like receptor 4 (TLR4) -/-ACAT1+/+ and TLR4-/-ACAT1-/- mice were subjected to bile duct ligation (BDL) for 3 weeks or were given carbon tetrachloride (CCl4) for 4 weeks to induce liver fibrosis. Results ACAT1 was the major isozyme in mice and human primary HSCs, and ACAT2 was the major isozyme in mouse primary hepatocytes and Kupffer cells. ACAT1 deficiency significantly exaggerated liver fibrosis in the mouse models of liver fibrosis, without affecting the degree of hepatocellular injury or liver inflammation, including hepatocyte apoptosis or Kupffer cell activation. ACAT1 deficiency significantly increased FC levels in HSCs, augmenting TLR4 protein and downregulating expression of transforming growth factor-β (TGFβ) pseudoreceptor Bambi (bone morphogenetic protein and activin membrane-bound inhibitor), leading to sensitization of HSCs to TGFβ activation. Exacerbation of liver fibrosis by ACAT1 deficiency was dependent on FC accumulation-induced enhancement of TLR4 signaling. Conclusions ACAT1 deficiency exaggerates liver fibrosis mainly through enhanced FC accumulation in HSCs. Regulation of ACAT1 activities in HSCs could be a target for treatment of liver fibrosis.

本文言語English
ページ(範囲)98-106
ページ数9
ジャーナルJournal of Hepatology
61
1
DOI
出版ステータスPublished - 2014 7

ASJC Scopus subject areas

  • 肝臓学

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