Fibroblast growth factor 21 deficiency exacerbates chronic alcohol-induced hepatic steatosis and injury
Open accessAbstract
Fibroblast growth factor 21 (FGF21) is a hepatokine that regulates glucose and lipid metabolism in the liver. We sought to determine the role of FGF21 in hepatic steatosis in mice exposed to chronic alcohol treatment and to discern underlying mechanisms. Male FGF21 knockout (FGF21 KO) and control (WT) mice were divided into groups that were fed either the Lieber DeCarli diet containing 5% alcohol or an isocaloric (control) diet for 4 weeks. One group of WT mice exposed to alcohol received recombinant human FGF21 (rhFGF21) in the last 5 days. Liver steatosis and inflammation were assessed. Primary mouse hepatocytes and AML-12 cells were incubated with metformin or rhFGF21. Hepatic genes and the products involved in in situ lipogenesis and fatty acid β-oxidation were analyzed. Alcohol exposure increased circulating levels and hepatic expression of FGF21. FGF21 depletion exacerbated alcohol-induced hepatic steatosis and liver injury, which was associated with increased activation of genes involved in lipogenesis mediated by SREBP1c and decreased expression of genes involved in fatty acid β-oxidation mediated by PGC1α. rhFGF21 administration reduced alcohol-induced hepatic steatosis and inflammation in WT mice. These results reveal that alcohol-induced FGF21 expression is a hepatic adaptive response to lipid dysregulation. Targeting FGF21 signaling could be a novel treatment approach for alcoholic steatohepatitis.
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Fgf21 knockout mice exhibit increased hepatic lipogenesis and decreased β-oxidation following alcohol exposure.
“Fgf21 knockout mice exhibit increased hepatic lipogenesis and decreased β-oxidation following alcohol exposure (83).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [83]
Pharmacological administration of FGF21 for 5 days to wild-type mice chronically fed alcohol significantly attenuated hepatic steatosis and liver injury.
“Importantly, pharmacological administration of FGF21 for 5 days to wild-type mice that were chronically fed alcohol significantly attenuated hepatic steatosis and liver injury (83).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [83]
Alcohol consumption robustly increases FGF21, largely by the liver.
“another nutritional intervention was shown to robustly increase FGF21: alcohol consumption. Ample evidence, in both rodents and humans, demonstrates that ethanol intake increases FGF21 production, largely by the liver”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [168]
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- Authors
- Liu, Y., Zhao, C., Xiao, J., Liu, L., Zhang, M., Wang, C., Wu, G., Zheng, M.-H., Xu, L.-M., Chen, Y.-P., Mohammadi, M., Chen, S.-Y., Cave, M., McClain, C., Li, X., & Feng, W.
- Affiliations
- University of Louisville (US)
- Wenzhou Medical University (CN)
- Northwest University (CN)
- New York University (US)
- Wenzhou University (CN)
- Corresponding author
- Feng, Wenke
- ORCID
- Venue
- Scientific Reports
- Published
- 2016-08-08
- Volume
- 6
- Issue
- 1
- Pages
- 31026-31026
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4976373
- OpenAlex
- W2520396611
- Cited by
- 78
- References
- 45
- Citations by year
- 2026: 1 · 2025: 10 · 2024: 10 · 2023: 10 · 2022: 11 · 2021: 3 · 2020: 9 · 2019: 7 · 2018: 10 · 2017: 3 · 2016: 3
- FWCI
- 3.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association (1-12-BS-47, 81170203, 81370481)
- National Natural Science Foundation of China (P20GM113226, 81370481, 1U01AA021901, 81500665, R21AA022416, R21AA020848, LY15H030017, LQ15H030006, 81570514, 81300311, R01AA023190, 1-12-BS-47, 81500477, 81170203)
- National Institutes of Health (81170203, 81370481, 1-12-BS-47)
- National Institute on Alcohol Abuse and Alcoholism (R01AA020265, R01AA018016, R01AA023681, R37AA010762, U01AA021901, R01AA021434, R01AA023190, K23AA018399, P01AA017103, R01AA018869, R21AA020848, R21AA022416, P50AA024337)
- National Institute of General Medical Sciences (P20GM113226)
- National Institute of Environmental Health Sciences (R01ES021375)
- National Institute of Dental and Craniofacial Research (R01DE013686)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Keywords
- FGF21, alcoholic liver disease, hepatic steatosis, chronic alcohol consumption, FGF21 knockout mice, lipogenesis, SREBP-1c, fatty acid beta-oxidation, PGC-1α, liver inflammation, metformin, hepatokines, Lieber-DeCarli diet
- MeSH terms
- Alcohol Drinking, Animals, Drug Evaluation, Preclinical, Fatty Liver, Alcoholic, Fibroblast Growth Factors, Humans, Liver, Male, Mice, Inbred C57BL, Oxidation-Reduction, Recombinant Proteins, Tumor Necrosis Factor-alpha, Interleukin-6, Gene Expression, Mice, Knockout, Chemokine CCL2, Lipogenesis
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