Activation of Adiponectin Receptors Induces Proprotein Convertase Subtilisin Kexin Type 9 Expression by Activating PPARgamma Pathway

Adiponectin is a hormone derived from adipose tissues. Reduced adiponectin levels have been determined to be associated with the occurrence of obesity‐linked diseases including insulin resistance/type 2 diabetes and atherosclerosis. Adiponectin exerts its functions by activating the adiponectin receptors (AdipoRs). Proprotein convertase subtilisin kexin type 9 (PCSK9) facilitates the development of atherosclerosis by enhancing the degradation of low‐density lipoprotein receptor (LDLR) protein to increase the circulating LDL‐cholesterol levels. PCSK9 expression is regulated by peroxisome proliferator‐activated receptor gamma (PPARgamma) and sterol regulatory element‐binding protein 2 (SREBP2). However, it remains unknown if activation of AdipoRs can influence PCSK9 expression and its function. Herein, we report that activation of AdipoRs induced PCSK9 expression through activation of the PPARgamma pathway. At molecular and cellular levels, we determined that activation of AdipoRs induced PCSK9 promoter activity, mRNA and protein expression in HepG2 cells. Although PPARgamma expression and SREBP2 translocation can be induced by activation of AdipoRs, the promoter analysis demonstrated that the mutation of PPAR‐responsive elements (PPRE), but not the sterol regulatory element (SRE) in PCSK9 promoter, attenuated the AdipoRs activation induced PCSK9 promoter activity which indicates that activation of PPARgamma dominates AdipoRs induced PCSK9 expression. Meanwhile, we determined that LDLR expression was increased which was due to that activation of AdipoRs induced SREBP2 translocation and enhanced PPARgamma mediated SREBP2 processing. In addition, we found that activation of AMPKalpha was also involved in AdipoRs regulated PCSK9 and LDLR expression in HepG2 cells. In vivo , administration of AdipoRs activators increased PCSK9 and LDLR expression in mouse liver and enhanced PCSK9 secretion. Our results indicate that although AdipoRs activation increased PCSK9 expression, it simultaneously induced LDLR expression and the induction of LDLR expression can still partially make contribution to the anti‐atherosclerotic properties of adiponectin.