Deficiency of fibroblast growth factor 21 (FGF21) promotes hepatocellular carcinoma (HCC) in mice on a long term obesogenic diet
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OBJECTIVE: Non-alcoholic fatty liver (NAFL) associated with obesity is a major cause of liver diseases which can progress to non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Fibroblast growth factor 21 (FGF21) plays an important role in liver metabolism and is also a potential marker for NAFL. Here we aimed to test the effect of FGF21 deficiency on liver pathology in mice consuming a conventional high fat, high sucrose (HFHS) obesogenic diet for up to 52 weeks. METHODS: C57BL6 WT and FGF21 KO mice were fed a conventional obesogenic diet and were evaluated at 16 and 52 weeks. Evaluation included metabolic assessment, liver pathology, and transcriptomic analysis. RESULTS: With consumption of HFHS diet, FGF21 deficient mice (FGF21 KO) develop excess fatty liver within 16 weeks. Hepatic pathology progresses and at 52 weeks FGF21 KO mice show significantly worse fibrosis and 78% of mice develop HCC; in contrast only 6% of WT mice develop HCC. Well differentiated hepatocellular carcinomas in FGF21 KO mice were characterized by expanded hepatic plates, loss of reticulin network, cytologic atypia, and positive immunostaining for glutamine synthetase. Microarray analysis reveals enrichment of several fibroblast growth factor signaling pathways in the tumors. CONCLUSIONS: In addition to attenuating inflammation and fibrosis in mice under a number of dietary challenges, we show here that FGF21 is required to limit the progression from NAFL to HCC in response to prolonged exposure to an obesogenic diet. The induction of hepatic FGF21 in response to the high fat, high sucrose obesogenic diet may play an important role in limiting progression of liver pathology from NAFL to HCC.
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FGF21 seems to serve as a protective factor that limits hepatic toxicity and dysfunction.
“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 [168]
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- Authors
- Singhal, G., Kumar, G., Chan, S., Fisher, F. M., Ma, Y., Vardeh, H. G., Nasser, I. A., Flier, J. S., & Maratos-Flier, E.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Emory University (US)
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 13
- Pages
- 56-66
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC6026320
- OpenAlex
- W2791134623
- Cited by
- 87
- References
- 60
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 7 · 2023: 7 · 2022: 15 · 2021: 14 · 2020: 18 · 2019: 11 · 2018: 2
- FWCI
- 4.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (R01 DK028082-035)
- 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 › Hepatology › Liver physiology and pathology
- Keywords
- FGF21, hepatocellular carcinoma, non-alcoholic fatty liver disease, obesogenic diet, high-fat high-sugar diet, hepatic steatosis, liver fibrosis, FGF21 knockout mice, FGF signaling, glutamine synthetase, liver cancer progression
- MeSH terms
- Animals, Fibroblast Growth Factors, Carcinoma, Hepatocellular, Liver, Liver Cirrhosis, Liver Neoplasms, Male, Mice, Inbred C57BL, Obesity, Mice, Knockout, Mice, Diet, High-Fat, Non-alcoholic Fatty Liver Disease
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