ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR229/006/SRR22972506/SRR22972506.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR229/003/SRR22972503/SRR22972503.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR229/008/SRR22972508/SRR22972508.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR229/012/SRR22972512/SRR22972512.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR229/001/SRR22972501/SRR22972501.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR229/002/SRR22972502/SRR22972502.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR229/007/SRR22972507/SRR22972507.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR229/010/SRR22972510/SRR22972510.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR229/099/SRR22972499/SRR22972499.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR229/005/SRR22972505/SRR22972505.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR229/004/SRR22972504/SRR22972504.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR229/000/SRR22972500/SRR22972500.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR229/098/SRR22972498/SRR22972498.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR229/011/SRR22972511/SRR22972511.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR229/013/SRR22972513/SRR22972513.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR229/009/SRR22972509/SRR22972509.fastq.gzprimaryOK200GenomicsBioinformatics and Biostatistics Core, Joslin Diabetes Centerhttps://www.ebi.ac.uk/ena/browser/view/PRJNA918408Mus musculusxref:PubMed:36586437Nonalcoholic 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. Overall design: 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 the liver.ENAfalseLiver-specific FGFR4 knockdown in mice on a HFD increases bile acid synthesis and improves hepatic steatosisLiver-specific FGFR4 knockdown in mice on a HFD increases bile acid synthesis and improves hepatic steatosis2025-09-242023-01-08PRJNA918408GSE2221711009036586437