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

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• 作者：Kengo Tomita¹ ; ² ; ^&dagger ; ; ^{kengo@ndmc.ac.jp" class="auth_mail} ; Toshiaki Teratani² ; ^&dagger ; ; Takahiro Suzuki² ; Motonori Shimizu¹ ; Hirokazu Sato¹ ; Kazuyuki Narimatsu¹ ; Shingo Usui¹ ; Hirotaka Furuhashi¹ ; Akifumi Kimura³ ; Kiyoshi Nishiyama³ ; Tadashi Maejima³ ; Yoshikiyo Okada¹ ; Chie Kurihara¹ ; Katsuyoshi Shimamura² ; Hirotoshi Ebinuma² ; Hidetsugu Saito⁴ ; Hirokazu Yokoyama⁵ ; Chikako Watanabe¹ ; Shunsuke Komoto¹ ; Shigeaki Nagao¹ ; Kazuo Sugiyama² ; Suefumi Aosasa³ ; Kazuo Hatsuse³ ; Junji Yamamoto³ ; Toshifumi Hibi² ; Soichiro Miura¹ ; Ryota Hokari¹ ; Takanori Kanai²
• 关键词：HSC ; hepatic stellate cell ; FC ; free cholesterol ; TLR4 ; Toll-like receptor 4 ; Bambi ; bone morphogenetic protein and activin membrane-bound inhibitor ; TGF ; transforming growth factor ; CE ; cholesterol ester ; ACAT ; acyl-coenzyme A ; cholesterol acyltransferase ; M尾CD ; methyl-尾-cyclodextrin ; LPS ; lipopolysaccharide ; CCl4 ; carbon tetrachloride ; BDL ; bile duct ligation ; ALT ; alanine aminotransferase ; HE ; hematoxylin-eosin ; SMA ; smooth muscle actin ; TUNEL ; terminal deoxynucleotidyl transferase-mediated de
• 刊名：Journal of Hepatology
• 出版年：July 2014
• 年：2014
• 卷：61
• 期：1
• 页码：98-106
• 全文大小：1852 K

文摘

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