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

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

来源：Journal of Hepatology, 2014, 61(1): 98-106.

DOI：10.1016/j.jhep.2014.03.018

• Acyl-coenzyme A:cholesterol acyltransferase
• Free cholesterol
• Hepatic stellate cell
• Toll-like receptor 4
• Bone morphogenetic protein and activin membrane-bound inhibitor
• Transforming growth factor-beta

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-beta (TGF beta) pseudoreceptor Bambi (bone morphogenetic protein and activin membrane-bound inhibitor), leading to sensitization of HSCs to TGF beta 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.

• 出版日期2014-7