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Irisin Is Controlled by Farnesoid X Receptor and Regulates Cholesterol Homeostasis
Hong Li1,2, Jing Shen1,2, Tong Wu1,2
1Department of Pharmacy, State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Objective:
The 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 Results:
We 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.
Conclusion:
Activation 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.
Insights
Activation of the farnesoid X receptor (FXR) boosts FNDC5/Irisin. This study shows Irisin improves hyperlipidemia and atherosclerosis in mice, suggesting it as a potential therapeutic strategy.
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.
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