Statins, but not proprotein convertase subtilisin‐kexin type 9 inhibitors, lower chemerin in hypercholesterolemia via low‐density lipoprotein receptor upregulation

Abstract

AbstractHypercholesterolemia is characterized by elevated low‐density lipoprotein (LDL)‐cholesterol levels and an increased risk of cardiovascular disease. The adipokine chemerin is an additional risk factor. Here we investigated whether cholesterol‐lowering with statins or proprotein convertase subtilisin‐kexin type 9 inhibitors (PCSK9i) affects chemerin. Both statins and PCKS9i lowered plasma LDL‐cholesterol, triglycerides and total cholesterol in hypercholesterolemic patients, and increased high‐density lipoprotein (HDL)‐cholesterol. Yet, only statins additionally reduced chemerin and high‐sensitivity C‐reactive protein (hsCRP). Applying PCSK9i on top of statins did not further reduce chemerin. Around 20% of chemerin occurred in the HDL2/HDL3 fractions, while >75% was free. Statins lowered both HDL‐bound and free chemerin. Pull‐down assays revealed that chemerin binds to the HDL‐component Apolipoprotein A‐I (ApoA‐I). The statins, but not PCSK9i, diminished chemerin secretion from HepG2 cells by upregulating LDL receptor mRNA. Furthermore, chemerin inhibited HDL‐mediated cholesterol efflux via its chemerin chemokine‐like receptor 1 in differentiated macrophages. In conclusion, statins, but not PCSK9i, lower circulating chemerin by directly affecting its release from hepatocytes. Chemerin binds to ApoA‐I and inhibits HDL‐mediated cholesterol efflux. Statins prevent this by lowering HDL‐bound chemerin. Combined with their anti‐inflammatory effect evidenced by hsCRP suppression, this represents a novel cardiovascular protective function of statins that distinguishes them from PCSK9i.