Gastroenterology

Gastroenterology

Volume 147, Issue 5, November 2014, Pages 1073-1083.e6
Gastroenterology

Original Research
Full Report: Basic and Translational—Liver
Fibroblast Growth Factor 21 Limits Lipotoxicity by Promoting Hepatic Fatty Acid Activation in Mice on Methionine and Choline-Deficient Diets

https://doi.org/10.1053/j.gastro.2014.07.044Get rights and content

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.

Section snippets

Mouse Maintenance and Experiments

All procedures were approved by the Beth Israel Deaconess Medical Center Institutional Animal Care and Use Committee. Mice were housed in groups of 2–4 mice at 24°C under a 12-hour light-dark cycle (6:00 am to 6:00 pm), with ad libitum access to food and water. Mice were fed either an MCD diet (TD.90262; Harlan Teklad, Indianapolis, IN), the matched control diet (TD.94149; Harlan Teklad), or a high-fat diet (D12451; Research Diets, New Brunswick, NJ) for either 4, 8, or 16 weeks. Mice were

Hepatic FGF21 Expression Is Increased During MCD-Induced Steatohepatitis

FGF21-KO mice fed a high-fat diet for 16 weeks showed evidence of exacerbated fibrosis and inflammation (Supplementary Figure 1), however, the phenotype was mild in both the WT and FGF21-KO mice. Because we were interested in the role of FGF21 in attenuating the more severe pathologies associated with NASH such as lipotoxicity and inflammation, we fed mice an MCD diet (Figure 1). Consumption of the MCD diet led to the development of fatty liver independent of obesity and was associated with a

Conclusions

FGF21 is a novel metabolic regulator that has potent effects on glucose and lipid homeostasis. Administration of FGF21 reduces circulating triglyceride levels, non-esterified fatty acids, and glucose levels, and leads to weight loss in obese animals. This occurs through enhanced insulin sensitivity and increased adipose tissue energy expenditure22 caused, in part, by increased white adipose tissue thermogenesis.23 In human beings, an FGF21 analog was found to improve serum lipid profiles and

Acknowledgments

The authors are grateful for the help from Gary Cline at the Yale Mouse Metabolic Phenotyping Core and the technical assistance of Patrick Antonellis, Deanna Sverdlov, and Anisha Sharma.

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    Conflicts of interest These authors disclose the following: Alexei Kharitonenkov is an employee of Eli Lilly and Co, and Eleftheria Maratos-Flier has been a consultant for Novo/Nordisk and Novartis regarding fibroblast growth factor 21. The remaining authors disclose no conflicts.

    Funding Supported by grants R01 DK069983 and R37 DK28082 (J.S.F. and E.M.F.) and 5 T32 DK007760-12 (P.C.C.) from the National Institutes of Health.

    Author names in bold designate shared co-first authors.

    Authors share co-first authorship.

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