Abstract
ObjectiveThe aim of this study was to investigate whether the nuclear receptor farnesoid X receptor (FXR) could regulate FNDC5/Irisin expression and the role of Irisin in hyperlipidemia and atherosclerosis in ApoE-/- mice.Methods and ResultsWe treated primary human hepatocytes, HepG2 cells, and Rhesus macaques with FXR agonist (CDCA, GW4064, and ivermectin). FNDC5 expression was highly induced by CDCA and GW4064 in hepatocytes, HepG2 cells, and the circulating level of Irisin increased in Rhesus macaques. Luciferase reporter and CHIP assays were used to determine whether FXR could regulate FNDC5 promoter activity. Irisin-ApoE-/- and ApoE-/- mice were used to study the metabolic function of Irisin in dyslipidemia and atherosclerosis. Irisin-ApoE-/- mice showed improved hyperlipidemia and alleviated atherosclerosis as compared with ApoE-/- mice. Irisin upregulated the expression of Abcg5/Abcg8 in liver and intestine, which increased the transport of biliary cholesterol and fecal cholesterol output.ConclusionActivation of FXR induces FNDC5 mRNA expression in human and increased the circulating level of Irisin in Rhesus macaques. FNDC5/Irisin is a direct transcriptional target of FXR. Irisin may be a novel therapeutic strategy for dyslipidemia and atherosclerosis.
Highlights
Cholesterol plays an important role in cellular membranous structures
Cholesterol export is mediated by several membrane cholesterol transporters, Abbreviations: Abcg5/8, ATP-binding cassette transporters5/8; ApoE−/−, ApoE knockout; CAR, constitutive androstane receptor; CDCA, chenodeoxycholic acid; FNDC5, fibronectin type III domain-containing protein 5; Farnesoid X receptor (FXR), farnesoid X receptor; GW, GW3965; Irisin-TG, irisin transgenic mice; LXR, liver X receptor; Rif, rifamycin
We showed that FNDC5/Irisin is regulated by FXR
Summary
Cholesterol plays an important role in cellular membranous structures. Its metabolites, such as bile acids, oxysterols, certain vitamins, and steroid hormones, are essential for various cellular functions (Grebe and Latz, 2013). Cholesterol export is mediated by several membrane cholesterol transporters, Abbreviations: Abcg5/8, ATP-binding cassette transporters5/8; ApoE−/−, ApoE knockout; CAR, constitutive androstane receptor; CDCA, chenodeoxycholic acid; FNDC5, fibronectin type III domain-containing protein 5; FXR, farnesoid X receptor; GW, GW3965; Irisin-TG, irisin transgenic mice; LXR, liver X receptor; Rif, rifamycin. Abca plays a crucial role in the efflux of cellular cholesterol to APOA-I, whereas ABCG1 promotes cellular cholesterol export to high-density lipoprotein (HDL) (Ye et al, 2011)
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