{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Moreau F"],"funding":["NIDDK NIH HHS"],"pagination":["100324"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9871743"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["64(2)"],"pubmed_abstract":["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 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 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 high-fat diet-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."],"journal":["Journal of lipid research"],"pubmed_title":["Liver-specific FGFR4 knockdown in mice on an HFD increases bile acid synthesis and improves hepatic steatosis."],"pmcid":["PMC9871743"],"funding_grant_id":["P30 DK036836","R01 DK128429"],"pubmed_authors":["Kahn RC","Softic S","Clish C","Liu XY","Tremblay F","Avila-Pacheco J","Brunao BB","Moreau F","Fitzgerald K"],"additional_accession":[]},"is_claimable":false,"name":"Liver-specific FGFR4 knockdown in mice on an HFD increases bile acid synthesis and improves hepatic steatosis.","description":"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 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 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 high-fat diet-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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Dec","modification":"2025-04-04T20:35:32.433Z","creation":"2025-04-04T20:35:32.433Z"},"accession":"S-EPMC9871743","cross_references":{"pubmed":["36586437"],"doi":["10.1016/j.jlr.2022.100324"]}}