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

被引：76

作者：

Tomita, Kengo ^{[1
,2
]}

Teratani, Toshiaki ^{[2
]}

Suzuki, Takahiro ^{[2
]}

Shimizu, Motonori ^{[1
]}

Sato, Hirokazu ^{[1
]}

Narimatsu, Kazuyuki ^{[1
]}

Usui, Shingo ^{[1
]}

Furuhashi, Hirotaka ^{[1
]}

Kimura, Akifumi ^{[3
]}

Nishiyama, Kiyoshi ^{[3
]}

Maejima, Tadashi ^{[3
]}

Okada, Yoshikiyo ^{[1
]}

Kurihara, Chie ^{[1
]}

Shimamura, Katsuyoshi ^{[2
]}

Ebinuma, Hirotoshi ^{[2
]}

Saito, Hidetsugu ^{[4
]}

Yokoyama, Hirokazu ^{[5
]}

Watanabe, Chikako ^{[1
]}

Komoto, Shunsuke ^{[1
]}

Nagao, Shigeaki ^{[1
]}

Sugiyama, Kazuo ^{[2
]}

Aosasa, Suefumi ^{[3
]}

Hatsuse, Kazuo ^{[3
]}

Yamamoto, Junji ^{[3
]}

Hibi, Toshifumi ^{[2
]}

Miura, Soichiro ^{[1
]}

Hokari, Ryota ^{[1
]}

Kanai, Takanori ^{[2
]}

机构：

[1] Natl Def Med Coll, Dept Internal Med, Div Gastroenterol & Hepatol, Tokorozawa, Saitama 3598513, Japan

[2] Keio Univ, Sch Med, Dept Internal Med,Div Gastroenterol & Hepatol, Shinjuku Ku, Tokyo 1608582, Japan

[3] Natl Def Med Coll, Dept Surg, Tokorozawa, Saitama 3598513, Japan

[4] Keio Univ, Fac Pharm, Grad Sch Pharmaceut Sci, Minato Ku, Tokyo 1058512, Japan

[5] Keio Univ, Sch Med, Ctr Hlth, Shinjuku Ku, Tokyo 1608582, Japan

来源：

JOURNAL OF HEPATOLOGY | 2014年 / 61卷 / 01期

基金：

日本学术振兴会;

关键词：

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; ENDOPLASMIC-RETICULUM; ACAT INHIBITION; ATHEROSCLEROSIS; PROGRESSION; MECHANISMS; EFFLUX; TLR4;

D O I：

10.1016/j.jhep.2014.03.018

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

引用

页码：98 / 106

页数：9

共 28 条

[1] Massive xanthomatosis and altered composition of atherosclerotic lesions in hyperlipidemic mice lacking acyl CoA:cholesterol acyltransferase 1 [J].

Accad, M ;

Smith, SJ ;

Newland, DL ;

Sanan, DA ;

King, LE ;

Linton, MF ;

Fazio, S ;

Farese, RV .

JOURNAL OF CLINICAL INVESTIGATION, 2000, 105 (06) :711-719

[2] Liver fibrosis [J].

Bataller, R ;

Brenner, DA .

JOURNAL OF CLINICAL INVESTIGATION, 2005, 115 (02) :209-218

[3] Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II [J].

Bataller, R ;

Sancho-Bru, P ;

Ginès, P ;

Lora, JM ;

Al-Garawi, A ;

Solé, M ;

Colmenero, J ;

Nicolás, JM ;

Jiménez, W ;

Weich, N ;

Gutiérrez-Ramos, JC ;

Arroyo, V ;

Rodés, J .

GASTROENTEROLOGY, 2003, 125 (01) :117-125

[4]

Chang CCY, 2000, J BIOL CHEM, V275, P28083

[5] Cholesterol sensing, trafficking, and esterification [J].

Chang, Ta-Yuan ;

Chang, Catherine C. Y. ;

Ohgami, Nobutaka ;

Yamauchi, Yoshio .

ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, 2006, 22 :129-157

[6] Acyl-coenzyme A: cholesterol acyltransferases [J].

Chang, Ta-Yuan ;

Li, Bo-Liang ;

Chang, Catherine C. Y. ;

Urano, Yasuomi .

AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 2009, 297 (01) :E1-E9

[7] Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome -: A balancing act between plaque stability and rupture [J].

Dickhout, Jeffrey G. ;

Colgan, Stephen M. ;

Lhotak, Sarka ;

Austin, Richard C. .

CIRCULATION, 2007, 116 (11) :1214-1216

[8] ACAT1 deficiency disrupts cholesterol efflux and alters cellular morphology in macrophages [J].

Dove, DE ;

Su, YR ;

Zhang, WW ;

Jerome, WG ;

Swift, LL ;

Linton, MF ;

Fazio, S .

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2005, 25 (01) :128-134

[9] Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages [J].

Fazio, S ;

Major, AS ;

Swift, LL ;

Gleaves, LA ;

Accad, M ;

Linton, MF ;

Farese, RV .

JOURNAL OF CLINICAL INVESTIGATION, 2001, 107 (02) :163-171

[10] The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages [J].

Feng, B ;

Yao, PM ;

Li, YK ;

Devlin, CM ;

Zhang, DJ ;

Harding, HP ;

Sweeney, M ;

Rong, JX ;

Kuriakose, G ;

Fisher, EA ;

Marks, AR ;

Ron, D ;

Tabas, I .

NATURE CELL BIOLOGY, 2003, 5 (09) :781-792

← 1 2 3 →