Cited by 241Liver physiology and pathologyLiver Disease Diagnosis and TreatmentCholesterol and Lipid Metabolism

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A High-Cholesterol Diet Exacerbates Liver Fibrosis in Mice via Accumulation of Free Cholesterol in Hepatic Stellate Cells

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Teratani, Toshiaki, Tomita, Kengo, Suzuki, Takahiro, Oshikawa, Tetsuya, Yokoyama, Hirokazu, Shimamura, Katsuyoshi, Tominaga, Susumu, Hiroi, Sadayuki, Irie, Rie, Okada, Yoshikiyo, Kurihara, Chie, Ebinuma, Hirotoshi, Saito, Hidetsugu, Hokari, Ryota, Sugiyama, Kazuo, Kanai, Takanori, Miura, Soichiro, Hibi, Toshifumi·2012·Gastroenterology

DOI 10.1053/j.gastro.2011.09.049

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Abstract

Background & aims 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.

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Authors: Teratani, T., Tomita, K., Suzuki, T., Oshikawa, T., Yokoyama, H., Shimamura, K., Tominaga, S., Hiroi, S., Irie, R., Okada, Y., Kurihara, C., Ebinuma, H., Saito, H., Hokari, R., Sugiyama, K., Kanai, T., Miura, S., & Hibi, T.
Affiliations: Keio University (JP)
National Defense Medical College (JP)
Kawasaki Municipal Hospital (JP)
Corresponding author: Tomita, Kengo
ORCID: Tomita, Kengo
Suzuki, Takahiro
Irie, Rie
Okada, Yoshikiyo
Kurihara, Chie
Ebinuma, Hirotoshi
Saito, Hidetsugu
Hokari, Ryota
Venue: Gastroenterology
Publisher: Elsevier BV
Published: 2012-01
Volume: 142
Issue: 1
Pages: 152-164.e10
ISSN: 0016-5085 (ISSN-L)
DOI: 10.1053/j.gastro.2011.09.049
OpenAlex: W1996266503
Cited by: 241
References: 23
Citations by year: 2026: 15 · 2025: 21 · 2024: 22 · 2023: 25 · 2022: 22 · 2021: 15 · 2020: 20 · 2019: 14 · 2018: 13 · 2017: 8 · 2016: 19 · 2015: 16 · 2014: 7 · 2013: 14 · 2012: 9
FWCI: 6.22
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Gastroenterology (publishedVersion)
PubMed (publishedVersion)
Funders: Ministry of Education, Culture, Sports, Science and Technology
Topics: Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Keywords: dietary cholesterol, liver fibrosis, hepatic stellate cells, free cholesterol accumulation, TLR4, TGF-beta signaling, Niemann-Pick C1, bile duct ligation, carbon tetrachloride, hepatic fibrogenesis, antifibrotic therapy
MeSH terms: Niemann-Pick C1 Protein, Animals, Bile Ducts, Carbon Tetrachloride, Cholesterol, Dietary, Disease Models, Animal, Kupffer Cells, Ligation, Liver Cirrhosis, Male, Membrane Proteins, Mice, Inbred C3H, Mice, Inbred C57BL, Proteins, Time Factors, Signal Transduction, Transforming Growth Factor beta, Apoptosis, Mice, Knockout, Disease Progression, Intracellular Signaling Peptides and Proteins, Toll-Like Receptor 4, Mice, Niemann-Pick Disease, Type C, Hepatic Stellate Cells

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A High-Cholesterol Diet Exacerbates Liver Fibrosis in Mice via Accumulation of Free Cholesterol in Hepatic Stellate Cells

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