Liver-specific FGFR4 knockdown in mice on a HFD increases bile acid synthesis and improves hepatic steatosis II

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with increased risk in patients with metabolic syndrome. There are no FDA approved treatments, but farnesoid X receptor (FXR) agonists have shown promising results in clinical studies for NAFLD management. In addition to FXR, fibroblast growth factor receptor FGFR4 is a key mediator of hepatic bile acid synthesis. Using N-acetylgalactosamine-conjugated siRNA, we knocked down FGFR4 specifically in the liver of mice on chow or high-fat diet (HFD) and in mouse primary hepatocytes to determine the role of FGFR4 in metabolic processes and hepatic steatosis. Liver-specific FGFR4 silencing increased bile acid production and lowered serum cholesterol. Additionally, we found that HFD-induced liver steatosis and insulin resistance improved following FGFR4 knockdown. These improvements were associated with activation of the FXR-FGF15 axis in intestinal cells, but not in hepatocytes. We conclude that targeting FGFR4 in the liver to activate the intestinal FXR-FGF15 axis may be a promising strategy for the treatment of NAFLD and metabolic dysfunction. C57BL6/J male mice were placed on Chow (Mouse Diet 9F, PharmaServ) or 60% HFD (Research diets, D12492) for 12 weeks. The mice were injected subcutaneously with 3 mg/kg of GalNAc conjugated siRNA targeting FGFR4 or a sterile 0.9% sodium chloride solution (control) every two weeks while on the diets. Total RNA was isolated from small intestines.