Human Serum PCSK9 Is Elevated at Parturition in Comparison to Nonpregnant Subjects While Serum PCSK9 from Umbilical Cord Blood is Lower Compared to Maternal Blood
Background. Serum lipids including total cholesterol (TC), triglycerides (TG), and low density lipoprotein cholesterol (LDL-C) are increased in pregnancy. Serum proprotein convertase subtilisin kexin 9 (PCSK9) is a significant player in lipoprotein metabolism. Circulating PCSK9 downregulates the LDL receptor on the surface of the liver, inhibiting clearance of LDL-C. Therefore, our study assessed serum PCSK9 concentrations at parturition (Maternal) compared to a nonpregnant (Control) cohort, as well as between mother and newborn (Maternal and Newborn). Methods. Blood was collected from women at parturition and from umbilical cords. Serum lipids and PCSK9 were measured and data were analysed for significance by Mann-Whitney test at and presented as median levels. Spearman's correlations were made at a 95% confidence interval. Results. Serum PCSK9 was significantly higher in Maternal versus Control cohorts (493.1 versus 289.7？ng/mL; , resp.), while the Newborn cohort was significantly lower than Maternal (278.2 versus 493.1？ng/mL; , resp.). PCSK9 was significantly correlated with TC and HDL-C in Maternal and with TC, LDL-C, and HDL-C in Newborn cohorts. Conclusions. Our study provides the first quantitative report on PCSK9 in pregnancy (at parturition) and in umbilical cord blood. Further research will determine how these changes may affect lipoprotein levels during this physiological state. 1. Introduction Pregnancy is associated with steady increases in maternal serum concentrations of total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) from first to third trimester [1, 2]. Other changes include an increase in high density lipoprotein cholesterol (HDL-C), triglycerides (TG), serum apolipoprotein B (apoB), and apolipoprotein AI (apoAI) levels and a net increase in the apoB/apoAI ratio [1, 2]. In contrast, umbilical cord blood has lower lipid levels than adults, including TG, LDL-C, and HDL-C subfractions [3]. In addition, HDL is the major cholesterol-containing particle in cord blood, unlike adult blood where it is LDL [3]. The molecular mechanisms involving lipoprotein changes during pregnancy and their influence on cord blood levels have yet to be fully elucidated [3]. Proprotein convertase subtilisin kexin 9 (PCSK9), a secreted glycoprotein and member of the proprotein convertase family of mammalian serine proteases, has emerged as a significant player in lipoprotein metabolism since its discovery in 2003 [4]. Population studies have shown that PCSK9 gain of function variants associate with high LDL-C levels and autosomal dominant
References
[1]
J. C. Mazurkiewicz, G. F. Watts, F. G. Warburton, B. M. Slavin, C. Lowy, and E. Koukkou, “Serum lipids, lipoproteins and apolipoproteins in pregnant non-diabetic patients,” Journal of Clinical Pathology, vol. 47, no. 8, pp. 728–731, 1994.
[2]
W. Piechota and A. Staszewski, “Reference ranges of lipids and apolipoproteins in pregnancy,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 45, no. 1, pp. 27–35, 1992.
[3]
N. Bansal, J. K. Cruickshank, P. McElduff, and P. N. Durrington, “Cord blood lipoproteins and prenatal influences,” Current Opinion in Lipidology, vol. 16, no. 4, pp. 400–408, 2005.
[4]
N. G. Seidah, S. Benjannet, L. Wickham et al., “The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 3, pp. 928–933, 2003.
[5]
M. Abifadel, M. Varret, J. Rabès et al., “Mutations in PCSK9 cause autosomal dominant hypercholesterolemia,” Nature Genetics, vol. 34, no. 2, pp. 154–156, 2003.
[6]
K. M. Timms, S. Wagner, M. E. Samuels et al., “A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree,” Human Genetics, vol. 114, no. 4, pp. 349–353, 2004.
[7]
J. Cohen, A. Pertsemlidis, I. K. Kotowski, R. Graham, C. K. Garcia, and H. H. Hobbs, “Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9,” Nature Genetics, vol. 37, no. 2, pp. 161–165, 2005.
[8]
J. Mayne, T. Dewpura, A. Raymond et al., “Novel loss-of-function PCSK9 variant is associated with low plasma LDL cholesterol in a French-Canadian family and with impaired processing and secretion in cell culture,” Clinical Chemistry, vol. 57, no. 10, pp. 1415–1423, 2011.
[9]
J. Mayne, A. Raymond, A. Chaplin et al., “Plasma PCSK9 levels correlate with cholesterol in men but not in women,” Biochemical and Biophysical Research Communications, vol. 361, no. 2, pp. 451–456, 2007.
[10]
W. E. Alborn, G. Cao, H. E. Careskey et al., “Serum proprotein convertase subtilisin kexin type 9 is correlated directly with serum LDL cholesterol,” Clinical Chemistry, vol. 53, no. 10, pp. 1814–1819, 2007.
[11]
S. G. Lakoski, T. A. Lagace, J. C. Cohen, J. D. Horton, and H. H. Hobbs, “Genetic and metabolic determinants of plasma PCSK9 levels,” Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 7, pp. 2537–2543, 2009.
[12]
A. Baass, G. Dubuc, M. Tremblay et al., “Plasma PCSK9 is associated with age, sex, and multiple metabolic markers in a population-based sample of children and adolescents,” Clinical Chemistry, vol. 55, no. 9, pp. 1637–1645, 2009.
[13]
K. N. Maxwell and J. L. Breslow, “Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 18, pp. 7100–7105, 2004.
[14]
K. N. Maxwell, E. A. Fisher, and J. L. Breslow, “Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 6, pp. 2069–2074, 2005.
[15]
T. A. Lagace, D. E. Curtis, R. Garuti et al., “Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice,” Journal of Clinical Investigation, vol. 116, no. 11, pp. 2995–3005, 2006.
[16]
D. Zhang, T. A. Lagace, R. Garuti et al., “Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation,” Journal of Biological Chemistry, vol. 282, no. 25, pp. 18602–18612, 2007.
[17]
L. Persson, G. Cao, L. St？hle et al., “Circulating proprotein convertase subtilisin kexin type 9 has a diurnal rhythm synchronous with cholesterol synthesis and is reduced by fasting in humans,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 30, no. 12, pp. 2666–2672, 2010.
[18]
P. Costet, B. Cariou, G. Lambert et al., “Hepatic PCSK9 expression is regulated by nutritional status via insulin and sterol regulatory element-binding protein 1c,” Journal of Biological Chemistry, vol. 281, no. 10, pp. 6211–6218, 2006.
[19]
J. D. Browning and J. D. Horton, “Fasting reduces plasma proprotein convertase, subtilisin/kexin type 9 and cholesterol biosynthesis in humans,” Journal of Lipid Research, vol. 51, no. 11, pp. 3359–3363, 2010.
[20]
H. E. Careskey, R. A. Davis, W. E. Alborn, J. S. Troutt, G. Cao, and R. J. Konrad, “Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9,” Journal of Lipid Research, vol. 49, no. 2, pp. 394–398, 2008.
[21]
J. Davignon and G. Dubuc, “Statins and ezetimibe modulate plasma proprotein convertase subtilisin kexin-9 (PCSK9) levels,” Transactions of the American Clinical and Climatological Association, vol. 120, pp. 163–173, 2009.
[22]
J. Mayne, T. Dewpura, A. Raymond et al., “Plasma PCSK9 levels are significantly modified by statins and fibrates in humans,” Lipids in Health and Disease, vol. 11, no. 7, p. 22, 2008.
[23]
B. Verges, L. Duvillard, M. C. Brindisi et al., “Lack of association between plasma PCSK9 and LDL-apoB100 catabolism in patients with uncontrolled type 2 diabetes,” Atherosclerosis, vol. 219, no. 1, pp. 342–348, 2011.
[24]
E. Dube, M. Ethier-Chiasson, and J. Lafond, “Modulation of cholesterol transport by insulin-treated gestational diabetes mellitus in human full-term placenta,” Biology of Reproduction, vol. 88, no. 1, p. 16, 2013.
[25]
G. Dubuc, M. Tremblay, G. Paré et al., “A new method for measurement of total plasma PCSK9: clinical applications,” Journal of Lipid Research, vol. 51, no. 1, pp. 140–149, 2010.
[26]
T. Nakai, T. Tamai, and S. Yamada, “Plasma lipids and lipoproteins of Japanese adults and umbilical cord blood,” Artery, vol. 9, no. 2, pp. 132–150, 1981.
[27]
C. Catarino, I. Rebelo, L. Belo et al., “Relationship between maternal and cord blood hemostatic disturbances in preeclamptic pregnancies,” Thrombosis Research, vol. 123, no. 2, pp. 219–224, 2008.
[28]
V. A. Rodie, M. J. Caslake, F. Stewart et al., “Fetal cord plasma lipoprotein status in uncomplicated human pregnancies and in pregnancies complicated by pre-eclampsia and intrauterine growth restriction,” Atherosclerosis, vol. 176, no. 1, pp. 181–187, 2004.
[29]
S. Benjannet, D. Rhainds, R. Essalmani et al., “NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol,” Journal of Biological Chemistry, vol. 279, no. 47, pp. 48865–48875, 2004.
[30]
C. Gedeon, J. Behravan, G. Koren, and M. Piquette-Miller, “Transport of glyburide by placental ABC transporters: implications in fetal drug exposure,” Placenta, vol. 27, no. 11-12, pp. 1096–1102, 2006.
