The effect of fibroblast growth factor 15 deficiency on the development of high fat diet induced non-alcoholic steatohepatitis
Open accessAbstract
Non-alcoholic steatohepatitis (NASH) is a form of non-alcoholic fatty liver disease (NAFLD) characterized by steatosis, inflammation, and fibrosis often associated with metabolic syndrome. Fibroblast growth factor 15 (FGF15), an endocrine factor mainly produced in the distal part of small intestine, has emerged to be a critical factor in regulating bile acid homeostasis, energy metabolism, and liver regeneration. We hypothesized that FGF15 alters the development of each of the listed features of NASH. To test this hypothesis, four-week old male Fgf15-/- and their corresponding wild-type (WT) mice were fed either a high fat diet (HFD) or a control chow diet for six months. The results confirmed that HFD feeding for six months in WT mice recapitulated human NASH phenotype, including macrovesicular steatosis, inflammation, and fibrosis. Whereas FGF15 deficiency had no effect on the severity of liver steatosis or inflammation, it was associated with decreased liver fibrosis. Furthermore, FGF15 deficiency resulted in abnormal bile acid homeostasis, increased insulin resistance, increased HFD-induced serum triglycerides, decreased inductions of hepatic cholesterol content by HFD, and altered gene expression of lipid metabolic enzymes. These data suggest that FGF15 improves lipid homeostasis and reduces bile acid synthesis, but promotes fibrosis during the development of NASH.
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Previous research showed that fgf15−/− mice fed HFD for 24 weeks present more imbalanced bile acid profiles, more severe insulin resistance and higher serum triglycerides than HFD-fed WT mice.
“Previous research showed that fgf15−/− mice fed HFD for 24 weeks present more imbalanced bile acid profiles, more severe insulin resistance and higher serum triglycerides than HFD‐fed WT mice (Schumacher et al., 2017).”
From <i>Akkermansia muciniphila</i> alleviates <scp>high‐fat‐diet</scp> ‐related metabolic‐associated fatty liver disease by modulating gut microbiota and bile acids (2023) · cites this paper as Schumacher et al., 2017
The Methods (§2.1) describe six months of HFD feeding, and the Discussion (§4) summarizes abnormal bile acid homeostasis, increased insulin resistance, and higher serum triglycerides in Fgf15−/− mice. However, the Results (§3.1) call the HFD-group insulin-resistance difference only a trend (p = 0.06), so the claim presents it more firmly than the measured result warrants. The paper reports higher total serum bile acids (§3.2), not a measured bile-acid profile. (LLM, conf=0.84)
Experimental — accuracy not yet measuredFgf15−/− mice show overexpression of cd36, which acts as a main receptor of hepatocytes for the uptake of free fatty acids.
“Fgf15−/− mice show overexpression of cd36, which acts as a main receptor of hepatocytes for the uptake of free fatty acids (Schumacher et al., 2017).”
From <i>Akkermansia muciniphila</i> alleviates <scp>high‐fat‐diet</scp> ‐related metabolic‐associated fatty liver disease by modulating gut microbiota and bile acids (2023) · cites this paper as Schumacher et al., 2017
Results §3.1 reports greater Cd36 mRNA expression in Fgf15 knockout mice than in wild-type mice on both diets and describes Cd36 as a transporter for long-chain fatty acids. It does not establish that Cd36 is a main receptor specifically on hepatocytes for free-fatty-acid uptake, or that the higher mRNA expression means greater receptor abundance. (LLM, conf=0.87)
Experimental — accuracy not yet measuredFGF-15 -/- mice fed with a high fat diet showed decreased liver fibrosis compared to wildtype animals.
“FGF-15 -/-mice fed with a high fat diet showed decreased liver fibrosis compared to wildtype animals [75]”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [75]
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References 28 · Cited by 53
- Authors
- Schumacher, J. D., Kong, B., Pan, Y., Zhan, L., Sun, R., Aa, J., Rizzolo, D., Richardson, J. R., Chen, A., Goedken, M., Aleksunes, L. M., Laskin, D. L., & Guo, G. L.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- China Pharmaceutical University (CN)
- Rutgers Cancer Institute (US)
- Saint Louis University (US)
- Corresponding author
- Guo, G.L.
- ORCID
- Venue
- Toxicology and Applied Pharmacology
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 330
- Pages
- 1-8
- ISSN
- 0041-008X (ISSN-L)
- PMC
- PMC5812273
- OpenAlex
- W2731063128
- Cited by
- 53
- References
- 28
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 7 · 2021: 8 · 2020: 14 · 2019: 5 · 2018: 4
- FWCI
- 4.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Toxicology and Applied Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Funders
- National Institutes of Health (DK081343, DK090036, GM104037, ES-05022, 5T32ES007148)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- FGF15, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, high-fat diet, liver fibrosis, bile acid homeostasis, insulin resistance, liver cholesterol, lipid metabolism, steatosis, liver inflammation, serum triglycerides
- MeSH terms
- Animals, Bile Acids and Salts, Cholesterol, Fibroblast Growth Factors, Hepatitis, Homeostasis, Insulin Resistance, Liver, Liver Cirrhosis, Male, Mice, Inbred C57BL, Triglycerides, Mice, Knockout, Mice, Diet, High-Fat, Non-alcoholic Fatty Liver Disease
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