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

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)98-106
Number of pages9
JournalJournal of Hepatology
Volume61
Issue number1
DOIs
Publication statusPublished - 2014

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Hepatic Stellate Cells
Liver Cirrhosis
Cholesterol
Toll-Like Receptor 4
Kupffer Cells
Transforming Growth Factors
Isoenzymes
Hepatocytes
Sterol O-Acyltransferase
sterol O-acyltransferase 1
Activins
Acyl Coenzyme A
Bone Morphogenetic Proteins
Carbon Tetrachloride
Cholesterol Esters
Bile Ducts
Ligation
Down-Regulation
Apoptosis
Inflammation

Keywords

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

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

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

In: Journal of Hepatology, Vol. 61, No. 1, 2014, p. 98-106.

Research output: Contribution to journalArticle

Tomita, K, Teratani, T, Suzuki, T, Shimizu, M, Sato, H, Narimatsu, K, Usui, S, Furuhashi, H, Kimura, A, Nishiyama, K, Maejima, T, Okada, Y, Kurihara, C, Shimamura, K, Ebinuma, H, Saito, H, Yokoyama, H, Watanabe, C, Komoto, S, Nagao, S, Sugiyama, K, Aosasa, S, Hatsuse, K, Yamamoto, J, Hibi, T, Miura, S, Hokari, R & Kanai, T 2014, 'Acyl-CoA: cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells', Journal of Hepatology, vol. 61, no. 1, pp. 98-106. https://doi.org/10.1016/j.jhep.2014.03.018
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. / Acyl-CoA : cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells. In: Journal of Hepatology. 2014 ; Vol. 61, No. 1. pp. 98-106.
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abstract = "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.",
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T2 - cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells

AU - Tomita, Kengo

AU - Teratani, Toshiaki

AU - Suzuki, Takahiro

AU - Shimizu, Motonori

AU - Sato, Hirokazu

AU - Narimatsu, Kazuyuki

AU - Usui, Shingo

AU - Furuhashi, Hirotaka

AU - Kimura, Akifumi

AU - Nishiyama, Kiyoshi

AU - Maejima, Tadashi

AU - Okada, Yoshikiyo

AU - Kurihara, Chie

AU - Shimamura, Katsuyoshi

AU - Ebinuma, Hirotoshi

AU - Saito, Hidetsugu

AU - Yokoyama, Hirokazu

AU - Watanabe, Chikako

AU - Komoto, Shunsuke

AU - Nagao, Shigeaki

AU - Sugiyama, Kazuo

AU - Aosasa, Suefumi

AU - Hatsuse, Kazuo

AU - Yamamoto, Junji

AU - Hibi, Toshifumi

AU - Miura, Soichiro

AU - Hokari, Ryota

AU - Kanai, Takanori

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Acyl-coenzyme A:cholesterol acyltransferase

KW - Bone morphogenetic protein and activin membrane-bound inhibitor

KW - Free cholesterol

KW - Hepatic stellate cell

KW - Toll-like receptor 4

KW - Transforming growth factor-β

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