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Fibroblast Growth Factor 21 Limits Lipotoxicity by Promoting Hepatic Fatty Acid Activation in Mice on Methionine and Choline-Deficient Diets
Open accessAbstract
Background & aims Nonalcoholic fatty liver disease is a common consequence of human and rodent obesity. Disruptions in lipid metabolism lead to accumulation of triglycerides and fatty acids, which can promote inflammation and fibrosis and lead to nonalcoholic steatohepatitis. Circulating levels of fibroblast growth factor (FGF)21 increase in patients with nonalcoholic fatty liver disease or nonalcoholic steatohepatitis; therefore, we assessed the role of FGF21 in the progression of murine fatty liver disease, independent of obesity, caused by methionine and choline deficiency.Methods C57BL/6 wild-type and FGF21-knockout (FGF21-KO) mice were placed on methionine- and choline-deficient (MCD), high-fat, or control diets for 8-16 weeks. Mice were weighed, and serum and liver tissues were collected and analyzed for histology, levels of malondialdehyde and liver enzymes, gene expression, and lipid content.Results The MCD diet increased hepatic levels of FGF21 messenger RNA more than 50-fold and serum levels 16-fold, compared with the control diet. FGF21-KO mice had more severe steatosis, fibrosis, inflammation, and peroxidative damage than wild-type C57BL/6 mice. FGF21-KO mice had reduced hepatic fatty acid activation and β-oxidation, resulting in increased levels of free fatty acid. FGF21-KO mice given continuous subcutaneous infusions of FGF21 for 4 weeks while on an MCD diet had reduced steatosis and peroxidative damage, compared with mice not receiving FGF21. The expression of genes that regulate inflammation and fibrosis were reduced in FGF21-KO mice given FGF21, similar to those of wild-type mice.Conclusions FGF21 regulates fatty acid activation and oxidation in livers of mice. In the absence of FGF21, accumulation of inactivated fatty acids results in lipotoxic damage and increased steatosis.
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“Altogether, FGF21 seems to serve as a protective factor that limits hepatic toxicity [141,167] and dysfunction [168].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [167]
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Design and validation of a histological scoring system for nonalcoholic fatty liver disease†
Kleiner, D. E., Brunt, E. M., Van Natta, M., Behling, C., Contos, M. J., Cummings, O. W., Ferrell, L. D., Liu, Y., Torbenson, M. S., Unalp‐Arida, A., et al. (2005) · Hepatology · doi:10.1002/hep.20701 · Cited by 10,791
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FGF-21 as a novel metabolic regulator
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Pathogenesis of Liver Fibrosis
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FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis
Fisher, F. M., Kleiner, S., Douris, N., Fox, E. C., Mepani, R. J., Verdeguer, F., Wu, J., Kharitonenkov, A., Flier, J. S., Maratos-Flier, E., et al. (2012) · Genes & Development · doi:10.1101/gad.177857.111 · Cited by 1,478
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Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD
Montagner, A., Polizzi, A., Fouché, E., Ducheix, S., Lippi, Y., Lasserre, F., Barquissau, V., Régnier, M., Lukowicz, C., Benhamed, F., et al. (2016) · Gut · doi:10.1136/gutjnl-2015-310798 · Cited by 763
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The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic
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Metadata
- Authors
- Fisher, F. M., Chui, P. C., Nasser, I. A., Popov, Y., Cunniff, J. C., Lundasen, T., Kharitonenkov, A., Schuppan, D., Flier, J. S., & Maratos-Flier, E.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Eli Lilly (United States) (US)
- Corresponding author
- Fisher, Ffolliott M.
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 147
- Issue
- 5
- Pages
- 1073-1083.e6
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC4570569
- OpenAlex
- W1984913749
- Cited by
- 263
- References
- 44
- Citations by year
- 2026: 14 · 2025: 14 · 2024: 13 · 2023: 21 · 2022: 25 · 2021: 32 · 2020: 28 · 2019: 24 · 2018: 20 · 2017: 21 · 2016: 30 · 2015: 17 · 2014: 2
- FWCI
- 9.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- FGF21, lipotoxicity, non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, fatty acid beta-oxidation, hepatic steatosis, liver fibrosis, oxidative stress, free fatty acids, FGF21 knockout mice, high-fat diet
- MeSH terms
- Animals, Choline Deficiency, Disease Models, Animal, Fatty Acids, Fibroblast Growth Factors, Hepatitis, Liver, Liver Cirrhosis, Methionine, Mice, Inbred C57BL, Oxidation-Reduction, Recombinant Proteins, RNA, Messenger, Severity of Illness Index, Time Factors, Lipid Peroxidation, Mice, Knockout, Disease Progression, Inflammation Mediators, Infusions, Subcutaneous, Non-alcoholic Fatty Liver Disease
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