title: Acyl-CoA:cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: kengo@ndmc.ac.jp.
authors.forename: Kengo
authors.initials: K
authors.lastname: Tomita
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Teratani
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan.
authors.forename: Motonori
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Sato
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Narimatsu
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Usui
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Furuhashi
authors.affiliation: Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Kimura
authors.affiliation: Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Nishiyama
authors.affiliation: Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Maejima
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan.
authors.forename: Yoshikiyo
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Kurihara
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Shimamura
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Ebinuma
authors.affiliation: Graduate School of Pharmaceutical Sciences, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Saito
authors.affiliation: Health Center, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Yokoyama
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Watanabe
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Komoto
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan.
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Nagao
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sugiyama
authors.affiliation: Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan.
authors.forename: Suefumi
authors.initials: S
authors.lastname: Aosasa
authors.affiliation: Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hatsuse
authors.affiliation: Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Yamamoto
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hibi
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Miura
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Hokari
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D018450:Disease Progression; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D002785:Sterol O-Acyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D002788:Cholesterol Esters; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016212:Transforming Growth Factor beta; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; C493492:sterol O-acyltransferase 1
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