PCSK9 is Expressed in Human Visceral Adipose Tissue and Regulated by Insulin and Cardiac Natriuretic Peptides

• Published in: International journal of molecular sciences 2019-01, Vol.20 (2), p.245
• Main Authors: Bordicchia, Marica, Spannella, Francesco, Ferretti, Gianna, Bacchetti, Tiziana, Vignini, Arianna, Di Pentima, Chiara, Mazzanti, Laura, Sarzani, Riccardo
• Format: Article
• Language: English
• Subjects: ABCA1 protein; Activation; Adipocytes; Adipocytes - metabolism; Adipose tissue; Adipose tissue (brown); Adipose Tissue - metabolism; Aged; ATP-binding protein; Biomarkers; Body fat; Cholesterol; Cholesterol, LDL - blood; Efflux; Endoplasmic reticulum; Female; Gene expression; Gene Expression Regulation - drug effects; High density lipoprotein; HMG-CoA reductase inhibitors; Homeostasis; Humans; Hydroxymethylglutaryl-CoA reductase; Insulin; Insulin - pharmacology; Insulin resistance; Lipid Metabolism - drug effects; Lipids; Lipoproteins; Liver; Low density lipoprotein; Low density lipoprotein receptors; Male; Metabolic flux; Metabolism; Natriuretic Peptides - pharmacology; Peptides; Physiology; Plasma; Proprotein Convertase 9 - genetics; Proteins; Receptors, LDL - metabolism; Reductases; Scavenger receptors; Statins; Sterol regulatory element-binding protein; Triglycerides
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20020245

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to and degrades the low-density lipoprotein receptor (LDLR), contributing to hypercholesterolemia. Adipose tissue plays a role in lipoprotein metabolism, but there are almost no data about PCSK9 and LDLR regulation in human adipocytes. We studied PCSK9 and LDLR regulation by insulin, atrial natriuretic peptide (ANP, a potent lipolytic agonist that antagonizes insulin), and LDL in visceral adipose tissue (VAT) and in human cultured adipocytes. was expressed in VAT and its expression was positively correlated with body mass index (BMI). Both intracellular mature and secreted PCSK9 were abundant in cultured human adipocytes. Insulin induced PCSK9, LDLR, and sterol-regulatory element-binding protein-1c (SREBP-1c) and -2 expression (SREBP-2). ANP reduced insulin-induced PCSK9, especially in the context of a medium simulating hyperglycemia. Human LDL induced both mature and secreted PCSK9 and reduced LDLR. ANP indirectly blocked the LDLR degradation, reducing the positive effect of LDL on PCSK9. In conclusion, is expressed in human adipocytes. When the expression of PCSK9 is induced, LDLR is reduced through the PCSK9-mediated degradation. On the contrary, when the induction of PCSK9 by insulin and LDL is partially blocked by ANP, the LDLR degradation is reduced. This suggests that NPs could be able to control LDLR levels, preventing PCSK9 overexpression.