LI Dan,XIE Wei,YU Ning, et al. The role of FGF21 in regulating the ameliorative effect of fenofibrate on hepatic lipid metabolism[J]. JOURNAL OF WEZHOU MEDICAL UNIVERSITY, 2021, 51(10): 775-781.
Abstract：Objective: To investigate the regulating effect of fenofibrate on liver lipid metabolism in mice mediated by fibroblast growth factor 21 (FGF21). Methods: Experimental mice were divided into four groups, all fed a high-fat diet: wild-type control group (WT+HFD+CTL), wild-type fenofibrate treatment group (WT+HFD+FF), FGF21 knockout control group (FGF21 KO+HFD+CTL), FGF21 knockout fenofibrate treatment group (FGF21 KO+HFD+FF). ELISA was used to detect FGF21 and Adiponectin in mouse serum; HE and Oil Red O staining were used to detect hepatic morphological changes and lipid accumulation in liver tissue respectively;TG and TC assay kits were used to detect changes in serum TG and TC; qRT-PCR was used to detect the mRNA expression of PPARα, FGF21, hepatic cholesterol regulatory element binding protein Srebp-2, genes regulating lipid oxidation, catabolism and transport (Acaca, Acacb, ABCG5, ABCG8, Cyp7a1), PPARγ and Adiponectin.Results: Fenofibrate treatment for 4 weeks significantly up-regulated the expression levels of PPARα and FGF21 in mice liver, inhibited the increase of body mass, down-regulated the level of abnormal serum lipids and reduced the lipid deposition in liver (P<0.05). The protective effect induced by fenofibrate was somewhat diminished by the deletion of FGF21 gene. HE and Oil Red O staining showed that the knockdown of FGF21 gene diminished the ameliorative effect of fenofibrate on hepatic lipid accumulation in HFD-fed mice. In terms of molecularmechanisms, fenofibrate treatment significantly up-regulated the expression of metabolic regulatory genes (Acacb, ABCG5, Cyp7a1, etc.) for lipid oxidation, catabolism and transport, and down-regulated the expression of Srebp-2, a hepatic cholesterol regulatory element binding protein (P<0.05). However, these effects were significantly inhibited by FGF21 gene deletion (P<0.05). Meanwhile, FGF21 knockdown significantly inhibited fenofibrate induced upregulation of PPARγ and Adiponectin mRNA expression and elevated serum levels of Adiponectin (P<0.05). Conclusion: FGF21 mediates the biological effect of fenofibrate on anti-fatty liver lesions.
