The mechanisms of farnesoid X receptor-mediated protection against high-fat diet-induced hepatic lipid deposition in yellow catfish (Pelteobagrus fulvidraco)

High-fat diets (HFDs) are frequently used in aquaculture to enhance feed efficiency, yet they often induce hepatic steatosis by disrupting the balance between lipogenesis and lipolysis. In mammals, activation of the farnesoid X receptor (Fxr) alleviates hepatic lipid accumulation by modulating fibroblast growth factor 19 (Fgf19) expression, which in turn regulates lipid homeostasis. However, the molecular characteristics and regulatory mechanisms of Fgf19 in fishes remains poorly defined. In this study, we investigated the role of Fxr in hepatic lipid metabolism in yellow catfish ( Pelteobagrus fulvidraco ) fed a HFD, using the Fxr agonist GW4064. Our in vivo experiments demonstrated that while the HFD reduced growth and increased hepatic fat deposition, GW4064 supplementation reduced liver triglyceride and non-esterified fatty acid levels, restored the balance between lipogenesis and lipolysis, and alleviated oxidative stress. In vitro assays with primary hepatocytes confirmed these results, showing that Fxr activation via GW4064 lowered lipid accumulation and improved cellular redox status. Furthermore, the GW4064 treatment elevated the fgf19 and fgfr4 genes expression levels, and Fgf19 content. We also cloned the yellow catfish fgf19 gene and characterized a 1700 bp promoter region containing several transcription factor binding sites, including a critical Fxr element essential for fgf19 transcriptional activation. Deletion and mutational analysis revealed that Fxr directly activates fgf19 transcription by binding to the −354 to −345 bp site of the fgf19 gene promoter. Recombinant Fgf19 application reduced lipid deposition in hepatocytes by modulating key lipogenic and lipolytic genes, an effect that was disrupted upon inhibition of fibroblast growth factor receptor 4 (Fgfr4). Collectively, our findings indicate that Fxr activation modulates liver lipid metabolism in yellow catfish via the Fgf19-Fgfr4 signaling axis, providing novel insights and a potential therapeutic target for combating fatty liver disease in aquaculture.