Circulating Proprotein Convertase Subtilisin Kexin Type 9 Has a Diurnal Rhythm Synchronous With Cholesterol Synthesis and Is Reduced by Fasting in Humans

Abstract

Objective-To gain insight into the function of proprotein convertase subtilisin kexin type 9 (PCSK9) in humans by establishing whether circulating levels are influenced by diurnal, dietary, and hormonal changes. Methods and Results-We monitored circulating PCSK9 in a set of dynamic human experiments and could show that serum PCSK9 levels display a diurnal rhythm that closely parallels that of cholesterol synthesis, measured as serum lathosterol. In contrast to these marked diurnal changes in cholesterol metabolism, serum low-density lipoprotein (LDL) cholesterol levels remained stable during the diurnal cycle. Depletion of liver cholesterol by treatment with the bile acid-binding resin, cholestyramine, abolished the diurnal rhythms of both PCSK9 and lathosterol. Fasting (Ͼ18 hours) strongly reduced circulating PCSK9 and lathosterol levels, whereas serum LDL levels remained unchanged. Growth hormone, known to be increased during fasting in humans, reduced circulating PCSK9 in parallel to LDL cholesterol levels. Conclusion-Throughout the day, and in response to fasting and cholesterol depletion, circulating PCSK9 displays marked variation, presumably related to oscillations in hepatic cholesterol that modify its activity in parallel with cholesterol synthesis. In addition to this sterol-mediated regulation, additional effects on LDL receptors may be mediated by hormones directly influencing PCSK9. Key Words: circulating PCSK9 Ⅲ cholesterol synthesis Ⅲ LDL cholesterol Ⅲ diurnal rhythm Ⅲ growth hormone Ⅲ cholesterol-lowering drugs Ⅲ lipoproteins G enetic variants of proprotein convertase subtilisin kexin type 9 (PCSK9) influence plasma low-density lipoprotein (LDL) cholesterol in humans, accounting for both hypercholesterolemia and hypocholesterolemia and altered coronary risk. 1,2 PCSK9 modulates the number of LDL receptors (LDLRs) by triggering the degradation of LDLRs. 3 Gain-offunction mutations in the PCSK9 gene produce a phenotype of familial hypercholesterolemia, 1 whereas loss-of-function mutations reduce plasma LDL cholesterol levels. 2 Circulating PCSK9 is largely derived from the liver, 4,5 and plasma levels relate to the hepatic expression of PCSK9. 6 -9 It is still unclear to what extent PCSK9 is physiologically regulated and if such regulation may influence plasma LDL cholesterol levels in humans. Novel therapies aiming at lowering serum LDL cholesterol by interfering with PCSK9 activity are under development. 10 Fasting plasma levels of PCSK9 correlate positively with LDL cholesterol levels in healthy and diabetic patients 7,[11][12][13][14] ; however, in the most extensive study, 7 with Ͼ3000 subjects, PCSK9 levels only predicted 7% of the variation in LDL cholesterol. In animals, the hepatic gene expression of PCSK9 is partly under hormonal control: treatment with glucagon or high-dose estrogen reduces PCSK9 mRNA and increases the number of LDLRs, 15 whereas insulin 15,16 and growth hormone (GH) 17 both increase PCSK9 mRNA levels in rat liver.The gene expressions of PCSK9, the LDLR and 3-hydroxy-3-...

FoxO3 Transcription Factor and Sirt6 Deacetylase Regulate Low Density Lipoprotein (LDL)-cholesterol Homeostasis via Control of the Proprotein Convertase Subtilisin/Kexin Type 9 (Pcsk9) Gene Expression

“…PCSK9 gene expression can be induced by insulin and pioglitazone and also can be suppressed by glucagon, bile acids, berberine, fibrate, and oncostatin M (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). PCSK9 protein levels decrease in the course of fasting and increase after feeding (22,27,29,(32)(33)(34).…”

“…PCSK9 protein levels decrease in the course of fasting and increase after feeding (22,27,29,(32)(33)(34). A number of transcription factors or cofactors have been shown to regulate the PCSK9 gene expression, including sterol-response element binding proteins (SREBP-1/ 2), hepatocyte nuclear factor 1A (HNF1A), farnesoid X receptor, peroxisome proliferator-activated receptor ␥, liver X receptor, and histone nuclear factor P (24,28,29,(33)(34)(35)(36)(37).…”

Novel Regulators of Low-Density Lipoprotein Receptor and Circulating LDL-C for the Prevention and Treatment of Coronary Artery Disease

“…Contradicting results have been reported from two different labs, suggesting that in PCSK9 deficient mice, there was either compromised or unchanged insulin sensitivity, as evaluated by an oral glucose tolerant test (Cui et al, 2010;Lakoski et al, 2009;Langhi et al, 2009;Mbikay et al, 2010). expression of PCSK9, which implies a physiological role of PCSK9 in maintaining a constant plasma cholesterol level during the daily fluctuation of cholesterol biosynthesis (Persson et al, 2010). In animal models and humans, fasting reduces SREBP2 activity, and the plasma PCSK9 level is reduced accordingly.…”

“…In animal models and humans, fasting reduces SREBP2 activity, and the plasma PCSK9 level is reduced accordingly. Re-feeding results in recovery of PCSK9 expression and circulating PCSK9 levels (Browning and Horton, 2010;Persson et al, 2010). PCSK9 is also reported to be regulated by insulin, LXRs, and the SREBP1c axis in cultured cells.…”

Does Evolocumab, as a PCSK9 Inhibitor, Ameliorate the Lipid Profile in Familial Hypercholesterolemia Patients? A Meta-Analysis of Randomized Controlled Trials

“…The expression of PCSK9 gene is controlled by intracellular cholesterol content (16). Therefore, cholesterol depletion through treatment with statins, ezetimibe and bile acid-binding resins, leads to PCSK9 upregulation (17)(18)(19)(20)(21). The transcription of PCSK9 and LDLRs are co-upregulated through the sterol regulatory element binding protein-2 (SREBP 2) pathway after treatment with statins and this reduces the therapeutic trait of statins (22,23).…”