ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR230/023/SRR23029623/SRR23029623.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR230/026/SRR23029626/SRR23029626.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR230/014/SRR23029614/SRR23029614.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR230/025/SRR23029625/SRR23029625.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR230/021/SRR23029621/SRR23029621.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR230/019/SRR23029619/SRR23029619.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR230/015/SRR23029615/SRR23029615.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR230/028/SRR23029628/SRR23029628.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR230/017/SRR23029617/SRR23029617.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR230/027/SRR23029627/SRR23029627.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR230/016/SRR23029616/SRR23029616.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR230/024/SRR23029624/SRR23029624.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR230/029/SRR23029629/SRR23029629.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR230/020/SRR23029620/SRR23029620.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR230/022/SRR23029622/SRR23029622.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR230/018/SRR23029618/SRR23029618.fastq.gzprimary200OKGenomicsBioinformatics and Biostatistics Core, Joslin Diabetes Centerhttps://www.ebi.ac.uk/ena/browser/view/PRJNA922215Mus musculusNonalcoholic 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 small intestines.xref:PubMed:36586437ENAfalseLiver-specific FGFR4 knockdown in mice on a HFD increases bile acid synthesis and improves hepatic steatosis IILiver-specific FGFR4 knockdown in mice on a HFD increases bile acid synthesis and improves hepatic steatosis II2025-09-242023-01-13PRJNA922215GSE2224991009036586437