Abstract 1023: Proprotein Convertase Subtilisin Kexin type 9 is repressed by the Peroxisome Proliferator Activated Receptor alpha ligand fenofibric acid.
Familial autosomal dominant hypercholesterolemia is characterized by high levels of cholesterol associated to LDL (LDLc), secondary to mutations in the LDL receptor, its ligand the apolipoprotein B or the Proprotein Convertase Subtilisin Kexin type 9 (PCSK9). PCSK9 is a natural inhibitor of the LDLr and its absence reduces the risk for cardiovascular disease and increases sensitivity to statins. We recently showed that PCSK9’s expression is upregulated by insulin and the Liver X Receptor ligand T0901317, via SREBP-1c, and that it is downregulated by fasting. Here we show that the SREBP-1c response element we isolated in PCSK9 proximal promoter is also a sterol responsive element and mediates a large part of the promoter’s activation by statins. The decrease observed in PCSK9 expression during fasting couldn’t be entirely attributed to variations in SREBPs. New investigations show that this down regulation also involves an active repression by PPARalpha. Indeed PCSK9 mRNA is 4 fold (p = 0.01) more abundant in wild type mice than in PPARalpha -/- mice, after a 24h-long fasting, although fed mice present similar mRNA and protein levels. In vitro, in human immortalized hepatocytes, the PPARalpha agonist fenofibric acid (250 μM) diminished PCSK9 mRNA content by 75% (p = 0.002), its protein content by 65 % (p = 0.006), and its autocatalytic activity by −30%, (p = 0.02), as reflected by the cleavage of a peptide corresponding to the autocatalytic cleavage site (Naureckiene S. et al. 2003 Arch. Biochem. Biophys. 420:55–67.). Fenofibric acid also prevented the Liver X Receptor-mediated activation of PCSK9 by T0901317. Among several PPAR agonist (ciprofibrate, clofibrate, gemfibrozil), fenofibric acid was the most efficient in reducing PCSK9 autocatalytic activity. These results suggest that fenofibric acid, or the next generation of PPARalpha agonists, might constitute good repressors of PCSK9 in humans.