Irisin inhibits PCSK9 expression through activating AMPK-SREBP2 pathway

Previous studies found that irisin attenuated the vascular wall inflammation caused by Oxidized low-density lipoprotein (ox-LDL), and recent experiments have shown that proprotein convertase subtilisin/kexin type 9 (PCSK9) can act on various cells in the vascular wall to induce inflammatory responses. But, the relationship between irisin and PCSK9 has not been reported. The aim of this study was to investigate the effect of irisin on PSCK9 in endothelial cells and hepatocytes under the induction of ox-LDL.

Experiments were performed using human umbilical vein endothelial cells and Hep G2, and cells were treated with irisin and (or) ox-LDL for evaluating expression of PCSK9 and downstream inflammatory proteins, while the expression levels of AMP-dependent protein kinase (AMPK) and sterol-regulatory element binding protein 2 (SREBP2) were also examined. Then Compound C was used to inhibit AMPK activation and SiAMPK for silencing of AMPK mRNA, and the above assays were also performed to deeply validate the role of the AMPK-SREBP2 pathway.

Irisin treatment significantly downregulated the expression of PCSK9 and inflammation-related proteins induced by ox-LDL, also restored the content of p-AMPK and reduced the SREBP2 content. After the use of Compound C or SiAMPK, the content of p-AMPK was obviously decreased, and the positive effect of irisin was greatly weakened.

This study demonstrates that irisin suppresses PCSK9 expression through the AMPK-SREBP2 pathway and ameliorates ox-LDL-induced endothelial cells inflammation.