A High-Cholesterol Diet Exacerbates Liver Fibrosis in Mice via Accumulation of Free Cholesterol in Hepatic Stellate Cells
Open accessAbstract
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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Increased cholesterol promotes MASH fibrosis through the TAZ/Indian hedgehog pathway.
“Increased cholesterol in turn promotes MASH fibrosis through the TAZ/Indian hedgehog pathway described above (232-234).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [232]
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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
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 142
- Issue
- 1
- Pages
- 152-164.e10
- ISSN
- 0016-5085 (ISSN-L)
- 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
- 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 › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Surgery › 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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