Irisin Inhibits Hepatic Cholesterol Synthesis via AMPK-SREBP2 Signaling

•Irisin inhibits hepatic cholesterol synthesis.•Irisin activates AMPK.•Irisin inhibits SREBP2 transcription and nuclear translocation.Irisin is a myokine released during exercise. Whether irisin contributes to the beneficial effects of exercise in reduction of blood cholesterol remains unknown. This study revealed that long-term infusion of irisin into obese mice ameliorated hypercholesterolemia and cholesterol content. The reduction of hepatic cholesterol induced by irisin may be mediated by activation of AMPK and subsequent suppression of SREBP2 transcription and nuclear translocation.

Irisin, a myokine released during exercise, promotes browning of subcutaneous adipose tissue and regulates energy homeostasis. Although exercise constantly reduces blood cholesterol, whether irisin is involved in the regulation of cholesterol remains largely unknown. In the present study, subcutaneous infusion of irisin for 2 weeks induced a reduction in plasma and hepatic cholesterol in high fat diet-induced obese (DIO) mice. These alterations were associated with an activation of 5′ AMP-activated protein kinase (AMPK) and inhibition of sterol regulatory element-binding transcription factor 2 (SREBP2) transcription and nuclear translocation. In primary hepatocytes from either lean or DIO mice, irisin significantly decreased cholesterol content via sequential activation of AMPK and inhibition of SREBP2. Suppression of AMPK by compound C or AMPKα1 siRNA blocked irisin-induced alterations in cholesterol contents and SREBP2. In conclusion, irisin could suppress hepatic cholesterol production via a mechanism dependent of AMPK and SREBP2 signaling. These findings suggest that irisin is a promising therapeutic target for treatment of hypercholesterolemia.

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