Role of fibroblast growth factor type 1 and 2 in carbon tetrachloride-induced hepatic injury and fibrogenesis
Open accessAbstract
Genomic ablation of hepatocyte-specific fibroblast growth factor receptor (FGFR)4 in mice revealed a role of FGF signaling in cholesterol and bile acid metabolism and hepatolobular restoration in response to injury without effect on liver development or hepatocyte proliferation. Although the potential role of all 23 FGF polypeptides in the liver is still unclear, the most widely studied prototypes, FGF1 and FGF2, are present and have been implicated in liver cell growth and function in vitro. To determine whether FGF1 and FGF2 play a role in response to injury and fibrosis, we examined the impact of both acute and chronic exposure to carbon tetrachloride (CCl(4)) in the livers of FGF1- and FGF2-deficient mice. After acute CCl(4) exposure, FGF1(-/-)FGF2(-/-) mice exhibited an accelerated release of serum alanine aminotransferase similar to FGFR4 deficiency, but no effect on overall hepatolobular restoration or bile acid metabolism. FGF1(-/-)FGF2(-/-) mice exhibited a normal increase in alpha-smooth muscle actin and desmin associated with activation and migration of hepatic stellate cells to damage, but a reduced level of hepatic stellate cell-derived matrix collagen alpha1(I) synthesis. Liver fibrosis resulting from chronic CCl(4) exposure was markedly decreased in the livers of FGF1/FGF2-deficient mice. These results suggest an agonist role for FGF1 and FGF2 in specifically insult-induced liver matrix deposition and hepatic fibrogenesis and a potential target for the prevention of hepatic fibrosis.
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Microbiota-associated molecular patterns such as bacterial lipopolysaccharide accumulate in the portal vein and act as ligands for TLR2 and TLR4, activating pro-inflammatory pathways that lead to secretion of cytokines and chemokines from various liver cell types including endothelia, myofibroblasts and hepatocytes.
“Microbiota-associated molecular patterns such as bacterial lipopolysaccharide accumulate in the portal vein and have been shown to act as ligands for TLR2 and TLR4. These activate pro-inflammatory pathways leading to secretion of cytokines and chemokines from various cell types in the liver, including endothelia, myofibroblasts and hepatocytes.125,149,150”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [125]
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- Authors
- Yu, C., Wang, F., Jin, C., Huang, X., Miller, D. L., Basilico, C., & McKeehan, W. L.
- Affiliations
- Texas A&M University System (US)
- New York University (US)
- Corresponding author
- McKeehan, Wallace L.
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2003-10
- Volume
- 163
- Issue
- 4
- Pages
- 1653-1662
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1868310
- OpenAlex
- W2083019610
- Cited by
- 167
- References
- 49
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 6 · 2022: 12 · 2021: 7 · 2020: 11 · 2019: 4 · 2018: 5 · 2017: 9 · 2016: 6 · 2015: 2 · 2014: 12 · 2013: 12 · 2012: 4
- FWCI
- 4.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (CA 59971, R01CA059971)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 35310, Z01DK047039, R01DK035310)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- fibroblast growth factor 1, fibroblast growth factor 2, carbon tetrachloride, liver fibrosis, liver injury, hepatic stellate cells, collagen deposition, FGF signaling, FGF receptor 4, bile acid metabolism
- MeSH terms
- Actins, Animals, Bile Acids and Salts, Carbon Tetrachloride, Drug Administration Schedule, Extracellular Matrix, Hepatectomy, Liver, Liver Cirrhosis, Liver Diseases, Liver Regeneration, Muscle, Smooth, Time Factors, Transforming Growth Factor beta, Fibroblast Growth Factor 1, Fibroblast Growth Factor 2, Mice, Knockout, Collagen Type I, Mice, Transforming Growth Factor beta1, Chemical and Drug Induced Liver Injury
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