The effect of insulin on circulating PCSK9 in postmenopausal obese women.
BACKGROUND
PCSK9 (proprotein convertase subtilisin/kexin type 9) promotes the degradation of the LDLR (LDL receptor) in hepatocytes, leading to an increase in plasma LDL-C (LDL cholesterol). Previous animal studies have shown that insulin stimulates PCSK9 transcription and observational human studies showed a positive correlation between plasma PCSK9 concentration and fasting insulinemia.


OBJECTIVE
The purpose of this study was to investigate the effects of chronic and acute hyperinsulinemia on PCSK9 in a large cohort of human subjects as well as at a cellular level.


METHODS
The in vivo effect of hyperinsulinemia on plasma PCSK9 concentration was studied using euglycemic-hyperinsulinemic clamps in 82 non-diabetic post-menopausal obese patients. We studied the in vitro effects of insulin stimulation on PCSK9 mRNA as well as on protein expression and secretion in HepG2 and Huh7 cells.


RESULTS
Analysis of the pre and post-clamp data revealed a 15.4% (p<0.001) lowering of plasma PCSK9 concentration after acute insulin induction. In vitro studies post-insulin stimulation showed that mRNA levels of PCSK9 reduced by 25% in HepG2 cells (p<0.027) and by 59% in Huh7 cells (p<0.01). Intracellular concentration of PCSK9 were 10% lower in HepG2 cells (p<0.05) and 35% lower in Huh7 cells (p<0.05).


CONCLUSIONS
Our results show an inhibitory effect of acute hyperinsulinemia on PCSK9 in humans both in vitro and in vivo. This data may assist in evaluating PCSK9 levels in individuals on insulin therapy.
Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal (IRCM), QC, Canada. Electronic address: zuhier.awan@ircm.qc.ca.
Zuhier
Z
Awan
Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal (IRCM), QC, Canada.
Geneviève
G
Dubuc
Platform for Research in Obesity, Metabolism and Diabetes (PROMD), Metabolic Unit Laboratory, Clinical Research Institute of Montreal (IRCM), QC, Canada; Department of Nutrition, Faculty of Medicine, University of Montreal, QC, Canada.
May
M
Faraj
Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal (IRCM), QC, Canada.
Robert
R
Dufour
Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal (IRCM), QC, Canada.
Nabil G
NG
Seidah
Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal (IRCM), QC, Canada.
Jean
J
Davignon
Platform for Research in Obesity, Metabolism and Diabetes (PROMD), Metabolic Unit Laboratory, Clinical Research Institute of Montreal (IRCM), QC, Canada; Department of Nutrition, Faculty of Medicine, University of Montreal, QC, Canada; Montreal Diabetes Research Center (MDRC) and Endocrinology Division of Montreal University Hospital (CHUM), QC, Canada.
Rémi
R
Rabasa-Lhoret
Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal (IRCM), QC, Canada; Platform for Research in Obesity, Metabolism and Diabetes (PROMD), Metabolic Unit Laboratory, Clinical Research Institute of Montreal (IRCM), QC, Canada; Department of Medicine, Faculty of Medicine, McGill University, QC, Canada.
Alexis
A
Baass
D000368:Aged; D015331:Cohort Studies; D005260:Female; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000627:therapeutic use*; D008875:Middle Aged; D017698:Postmenopause; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000097:blood* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000097:blood* / Q000235:genetics
D007328:Insulin; D012333:RNA, Messenger; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
Cholesterol; Euglycemic–hyperinsulinemic clamp; Insulin; Insulin resistance; PCSK9