Autocrine/paracrine fibroblast growth factor 1 (FGF1) enhances systemic lipid metabolism in rainbow trout fed with a high-fat diet by elevating uridine levels through the AMPK signaling pathway and activating the upp2 promoter via irf1

Abstract

Fibroblast growth factor 1 (FGF1) is recognized for its role in regulating vertebrate energy metabolism, yet its impact on metabolic fatty liver disease in fish remains unexamined. This study investigates the regulatory mechanism of the autocrine/paracrine cytokine FGF1 on systemic lipid metabolism in rainbow trout (Oncorhynchus mykiss) subjected to a high-fat diet (HFD). Experimental fish (540 in total) were divided between two dietary groups (low-fat diet (LFD) and HFD) and categorized into three treatment groups: LFD + PBS (LFD injected with PBS), HFD + PBS (HFD injected with PBS), and HFD + rFGF1 (HFD injected with recombinant FGF1 protein). Over a 6-week period on the HFD, rainbow trout demonstrated weight gain and signs of metabolic dysregulation. However, compared to the HFD + PBS group, exogenous rFGF1 administration significantly lowered hepatosomatic index (HSI), whole-body, muscle, and liver crude fat content, hepatic vacuole formation, serum triglyceride (TG), serum LDL-c, and the expression levels of fatty acid synthesis (fas) and transport genes (cd36, fatp6), while elevating HDL-c and the expression levels of fatty acid oxidation genes (cpt1a, pparα, and acox1) (P < 0.05), thereby alleviating HFD-induced lipid accumulation without a significant impact on body weight (P > 0.05). Serum metabolomic analysis indicated that rFGF1 significantly elevated serum uridine levels (P < 0.05), with uridine demonstrating a capacity to regulate hepatocyte lipid metabolism effectively. Furthermore, rFGF1 was shown to enhance hepatic uridine biosynthesis through the AMPK signaling pathway, concurrently modulating uridine catabolism by downregulating interferon regulatory factor 1 (irf1) and altering its transcriptional control of uridine phosphorylase 2 (upp2). These findings suggest that rFGF1 mitigates hepatic lipid accumulation in rainbow trout under an HFD by promoting uridine synthesis via the AMPK pathway and partially inhibiting uridine catabolism through IRF1-UPP2 signaling.