Statins, but not PCSK9 inhibitors, reduce the adipokine chemerin in familial hypercholesterolemia: Focus on lipoprotein subfractions

Background: Familial hypercholesterolemia (FH) is characterized by severe elevations in circulating LDL-cholesterol, and an increase in the risk of dyslipidemia-related cardiovascular disease (CVD). Chemerin, as a newly identified adipokine, is considered as an additional risk factor for CVD. Here we investigated whether it can be modified by cholesterol-lowering therapy. Methods: Lipoprotein subfractions were isolated by density gradient ultracentrifugation. Lipids and chemerin concentrations were determined both before and after cholesterol lowering with either a statin (atorvastatin, simvastatin, rosuvastatin, or fluvastatin) or a PCSK9 inhibitor (PCSK9i; alirocumab or evolocumab). Results: At baseline chemerin levels were 113±46 (statin group) and 95±44 (PCSK9i group) ng/ml, while triglyceride (TG) levels were 1.9±1.6 and 2.6±1.7 mmol/ml, high-density lipoprotein cholesterol (HDL-c) levels were 1.3±0.4 and 1.2±0.4 mmol/ml, and low-density lipoprotein cholesterol (LDL-c) levels were 5.7±1.5 and 4.9±1.4 mmol/ml (P=ns for difference between 2 groups). Chemerin correlated positively with triglycerides (r=0.45, P<0.005) and negatively with HDL-c (r=-0.33, P<0.01). Both statins and PCSK9i reduced LDL-c (by 41 and 62%, P<0.0001), triglycerides (by 13 and 19%, P<0.01), and increased HDL-c (by 8 and 23%, P<0.01), but only statins additionally reduced chemerin (by 35%, P<0.005). The lipoprotein subfraction profile revealed that chemerin accumulated particularly in the HDL3 fraction (containing >60% of all chemerin in lipoprotein subfractions), with approximately 30% being present in the HDL2 fraction, and approximately 3% in the LDL fraction. Statins reduced HDL3-c and HDL3-TG, and the level of chemerin bound to all subfractions. PCSK9i reduced HDL3-c but did not affect HDL3-TG or the level of chemerin bound to HDL3 and HDL2. Conclusions: Circulating chemerin occurs in different lipoprotein subfractions, accumulating particularly in the HDL3 fraction. Statins, but not PCSK9i, lowers chemerin, possibly by interfering with its levels across lipoprotein subfractions. This may represent a novel cardiovascular protective function of statins.