Plasma PCSK9 levels are significantly modified by statins and fibrates in humans

Abstract

BackgroundProprotein convertase subtilisin kexin-like 9 (PCSK9) is a secreted glycoprotein that is transcriptionally regulated by cholesterol status. It modulates levels of circulating low density lipoprotein cholesterol (LDLC) by negatively regulating low density lipoprotein receptor (LDLR) levels. PCSK9 variants that result in 'gain of function' have been linked to autosomal dominant hypercholesterolemia, while significant protection from coronary artery disease has been documented in individuals who carry 'loss of function' PCSK9 variants. PCSK9 circulates in human plasma, and we previously reported that plasma PCSK9 is positively correlated with total cholesterol and LDLC in men.ResultsHerein, we report the effects of two lipid-modulating therapies, namely statins and fibrates, on PCSK9 plasma levels in human subjects. We also document their effects on endogenous PCSK9 and LDLR expression in a human hepatocyte cell line, HepG2, using immunoprecipitation and immunoblot analyses. Changes in plasma PCSK9 following fenofibrate or gemfibrozil treatments (fibric acid derivatives) were inversely correlated with changes in LDLC levels (r = -0.558, p = 0.013). Atorvastatin administration (HMGCoA reductase inhibitor) significantly increased plasma PCSK9 (7.40%, p = 0.033) and these changes were inversely correlated with changes in LDLC levels (r = -0.393, p = 0.012). Immunoblot analyses of endogenous PCSK9 and LDLR expression by HepG2 cells in response to statins and fibrates showed that LDLR is more upregulated than PCSK9 by simvastatin (2.6× vs 1.5×, respectively at 10 μM), while fenofibrate did not induce changes in either.ConclusionThese results suggest that in vivo (1) statins directly increase PCSK9 expression while (2) fibrates affect PCSK9 expression indirectly through its modulation of cholesterol levels and (3) that these therapies could be improved by combination with a PCSK9 inhibitor, constituting a novel hypercholesterolemic therapy, since PCSK9 was significantly upregulated by both treatments.

Pcsk9

“…They have been shown to repress PCSK9 gene expression in a human hepatocyte cell line and isolated mouse hepatocytes, 85,86 but the WY14643 agonist had no effect on the level of PCSK9 mRNA in isolated hamster hepatocytes. 87 The reasons for this discrepancy are unclear as are those from clinical studies in fibrate-treated patients, showing increased plasma PCSK9 levels in most studies [88][89][90][91] and a decreased levels in another. 85 PPARγ ligands, 15d-PGJ1 or pioglitazone, have been shown to augment the level of PCSK9 mRNA in HepG2 cells.…”

“…123 Although statins directly increase PCSK9 mRNA expression, PPARα agonists, such as fibrates, indirectly affect PCSK9 expression through modulation of cholesterol levels. 88 In a randomized trial, although statins were shown to increase the levels of circulating PCSK9, the cholesterol absorption inhibitor ezetimibe had no effect on PCSK9. 124 Finally, in a study in which women underwent in vitro fertilization, high estrogens resulted in a reduction in VLDL, LDL, and PCSK9 levels.…”

Comparison of effects of bezafibrate and fenofibrate on circulating proprotein convertase subtilisin/kexin type 9 and adipocytokine levels in dyslipidemic subjects with impaired glucose tolerance or type 2 diabetes mellitus: Results from a crossover study

“…Statins have been known to increase the nuclear translocation of sterol-regulatory element binding protein-2 (SREBP-2), which activates not only the LDLR but also PCSK9 gene expression [4][5][6]. Subsequently, statins increases serum PCSK9 levels [5][6][7][8] and this increment may attenuate the LDL-C lowering effect of statins. It may in a part explain the rule of 6% for statins, which indicates that each doubling of the statin dose results in only about a 6% further decrease in LDL-C.…”

“…Recently, it was shown that fenofibrate suppressed PCSK9 expression at the promoter level and reduced statin-induced PCSK9 secretion in vitro [9], whereas, fenofibrate did not suppress and rather increased circulating PCSK9 level in several in vivo studies [8,10,11]. Bezafibrate is another widely used fibrate, and both of which have substantial triglyceride (TG)-reducing-effect and high-density lipoprotein cholesterol (HDL-C)-raising effect.…”

PCSK9 − „missing link“ der familiären Hypercholesterinämie

“…Herausragend und einzigartig ist die besonders ausgeprägte zusätzliche LDLSenkung bei Patienten unter einer bereits bestehenden Statintherapie. Dieses völ-lig neue und unerwartete Wirkprinzip ist wahrscheinlich auf den Befund zurückzuführen, dass die statininduzierte Produktion von LDL-Rezeptoren parallel auch zu einem Anstieg von PCSK9 im Plasma führt [43]. LDL-Rezeptorund PCSK9-Synthese werden beide über SREBP-2-abhängige Signalwege gesteuert, die unter einer Statintherapie hochreguliert werden.…”