Irisin Is Controlled by Farnesoid X Receptor and Regulates Cholesterol Homeostasis

Area of Science:

• Endocrinology
• Metabolic Diseases
• Molecular Biology

Background:

• The nuclear receptor farnesoid X receptor (FXR) plays a role in bile acid and lipid metabolism.
• FNDC5/Irisin is a myokine with potential metabolic benefits.

Purpose of the Study:

• To investigate if FXR regulates FNDC5/Irisin expression.
• To determine the role of Irisin in hyperlipidemia and atherosclerosis in ApoE-/- mice.

Main Methods:

• Treatment of human hepatocytes, HepG2 cells, and Rhesus macaques with FXR agonists (CDCA, GW4064, ivermectin).
• Luciferase reporter and Chromatin Immunoprecipitation (CHIP) assays to assess FXR-FNDC5 promoter interaction.
• Administration of Irisin to ApoE-/- mice to evaluate its effects on dyslipidemia and atherosclerosis.

Main Results:

• FXR agonists significantly induced FNDC5 expression in human cells and increased circulating Irisin levels in Rhesus macaques.
• Irisin administration in ApoE-/- mice led to improved hyperlipidemia and reduced atherosclerosis.
• Irisin upregulated hepatic and intestinal Abcg5/Abcg8 expression, enhancing biliary and fecal cholesterol excretion.

Conclusions:

• FXR activation directly induces FNDC5 mRNA expression and increases circulating Irisin levels.
• FNDC5/Irisin is identified as a direct transcriptional target of FXR.
• Irisin presents a promising novel therapeutic strategy for managing dyslipidemia and atherosclerosis.