Effects of intestine-specific deletion of fibroblast growth factor 15 on alcoholic liver disease development in mice

Abstract

Background and aims

Alcoholic liver disease (ALD) is an important and growing cause for the development of chronic liver diseases in the world. Bile acid (BA) levels are increased in patients with ALD and dysregulation of BA homeostasis worsens ALD. BA synthesis is critically regulated by fibroblast growth factor (FGF)15 in mice and FGF19 in humans. FGF15/19 are mainly produced in the ileum and their main function is to suppress BA synthesis in the liver through the activation of fibroblast growth factor receptor 4 (FGFR4) on hepatocytes. The effects of intestine-specific Fgf15 deficiency on the development of ALD were determined in the current study.

Methods

Enterocyte-specific Fgf15 knockout mice (Fgf15^int−/−) and the established mouse model by chronic and binge ethanol feeding (NIAAA model) were adapted in this study.

Results

The Fgf15^int−/− mice had increased BA pool size, consistent with negative effects of FGF15-FGFR4 signaling on BA synthesis. There were not obviously physical and hepatic histological abnormalities presented in Fgf15^int−/− mice compared to wild-type mice. Following alcohol treatment, the Fgf15^int−/− mice exhibited a higher degree of liver injury, increased hepatic expression of Cd14, a receptor for lipopolysaccharide expressed in the liver, and increased hepatic lipid levels. We did not observe alterations in the levels of fibrosis in the liver or expression of genes involved in hepatic fibrosis, regardless of genotypes or following the alcohol treatment.

Conclusions

FGF15 may prevent hepatic steatosis in the development of ALD in mice, and maintaining FGF19/FGFR4 signaling may be critical in the prevention and/or treatment of ALD in humans in the future.