title: A high-cholesterol diet exacerbates liver fibrosis in mice via accumulation of free cholesterol in hepatic stellate cells.
abstract: OBJECTIVE
  Some studies have indicated that dietary cholesterol has a role in the progression of liver fibrosis. We investigated the mechanisms by which dietary cholesterol might contribute to hepatic fibrogenesis.
  
  
  METHODS
  C57BL/6 mice were fed a high-cholesterol diet or a control diet for 4 weeks; liver fibrosis then was induced by bile-duct ligation or carbon tetrachloride administration. Hepatic stellate cells (HSCs) were isolated from mice fed high-cholesterol diets or from Niemann-Pick type C1-deficient mice, which accumulate intracellular free cholesterol.
  
  
  RESULTS
  After bile-duct ligation or carbon tetrachloride administration, mice fed high-cholesterol diets had significant increases in liver fibrosis and activation of HSCs compared with mice fed control diets. There were no significant differences in the degree of hepatocellular injury or liver inflammation, including hepatocyte apoptosis or Kupffer cell activation, between mice fed high-cholesterol or control diets. Levels of free cholesterol were much higher in HSCs from mice fed high-cholesterol diets than those fed control diets. In cultured HSCs, accumulation of free cholesterol in HSCs increased levels of Toll-like receptor 4 (TLR4), leading to down-regulation of bone morphogenetic protein and activin membrane-bound inhibitor (a pseudoreceptor for transforming growth factor [TGF]β); the HSCs became sensitized to TGFβ-induced activation. Liver fibrosis was not aggravated by the high-cholesterol diet in C3H/HeJ mice, which express a mutant form of TLR4; HSCs that express mutant TLR4 were not activated by accumulation of free cholesterol.
  
  
  CONCLUSIONS
  Dietary cholesterol aggravates liver fibrosis because free cholesterol accumulates in HSCs, leading to increased TLR4 signaling, down-regulation of bone morphogenetic protein and activin membrane-bound inhibitor, and sensitization of HSC to TGFβ. This pathway might be targeted by antifibrotic therapies.
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors: Toshiaki
authors: T
authors: Teratani
authors: Kengo
authors: K
authors: Tomita
authors: Takahiro
authors: T
authors: Suzuki
authors: Tetsuya
authors: T
authors: Oshikawa
authors: Hirokazu
authors: H
authors: Yokoyama
authors: Katsuyoshi
authors: K
authors: Shimamura
authors: Susumu
authors: S
authors: Tominaga
authors: Sadayuki
authors: S
authors: Hiroi
authors: Rie
authors: R
authors: Irie
authors: Yoshikiyo
authors: Y
authors: Okada
authors: Chie
authors: C
authors: Kurihara
authors: Hirotoshi
authors: H
authors: Ebinuma
authors: Hidetsugu
authors: H
authors: Saito
authors: Ryota
authors: R
authors: Hokari
authors: Kazuo
authors: K
authors: Sugiyama
authors: Takanori
authors: T
authors: Kanai
authors: Soichiro
authors: S
authors: Miura
authors: Toshifumi
authors: T
authors: Hibi
mesh_terms: D000818:Animals; D017209:Apoptosis; D001652:Bile Ducts / Q000601:surgery; D002251:Carbon Tetrachloride; D002791:Cholesterol, Dietary / Q000009:adverse effects* / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D007728:Kupffer Cells / Q000378:metabolism; D008026:Ligation; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C485672:Bambi protein, mouse; D002791:Cholesterol, Dietary; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016212:Transforming Growth Factor beta; D002251:Carbon Tetrachloride