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

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. PCSK9 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, PCSK9 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.

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Abstract 386: Thrombin Inhibition by Dabigatran Reduces the Amount of Pro-Inflammatory CD11c-Positive Macrophages in Visceral Adipose Tissue of Low-Density Lipoprotein Receptor-Deficient Mice

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.386 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Kathrin Feldmann ◽

Maria Grandoch ◽

Stefan Lehr ◽

Jens W Fischer

Keyword(s):

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Low Density ◽

Lipoprotein Receptor ◽

Thrombin Inhibition ◽

Diet Induced Obesity ◽

Density Lipoprotein Receptor ◽

Visceral Adipose

Thrombin is involved in inflammatory processes. In obesity, chronic low-grade inflammation promotes the development of insulin resistance and diabetes mellitus type 2 (T2DM) which strongly drive atherosclerosis. Patients with T2DM exhibit increased circulating levels of tissue factor as well as thrombin-antithrombin complexes. Aim of the present study was to analyse potential effects of thrombin inhibition by dabigatran on adipose tissue inflammation in a mouse-model of diet-induced obesity and atherosclerosis. Female, 10 weeks old low-density lipoprotein receptor-deficient (LDLR-/-) mice received a Western-type diet containing 5 mg/g dabigatran or matching placebo for 20 weeks. Flow cytometric analysis of the stromal vascular fraction revealed a reduction in pro-inflammatory macrophages (CD11b+F4/80+CD11c+) in visceral adipose tissue of dabigatran-treated animals (control 8.490 ± 1.996, dabigatran 3.606 ± 0.8884 CD11c+ macrophages/mg adipose tissue, n = 21), while the number of anti-inflammatory CD11c- macrophages was not changed. mRNA expression in the visceral adipose tissue as well as plasma concentrations of the pro-inflammatory cytokines interleukin (IL) 1 beta and IL 6 (quantitative real-time PCR (qPCR), multiplex immunoassay) were reduced in dabigatran-treated animals. No differences in body-weight gain and the amount of body fat (NMR measurement) were observed. Glucose tolerance and insulin resistance did not differ between groups, either. In vitro no direct influence of thrombin on macrophage polarization was detectable in bone marrow-derived macrophages (flow cytometry, qPCR). However, first results indicate that stimulation of the cells with conditioned medium from thrombin-treated, differentiated preadipocytes (3T3L1 cells) enhances M1 polarization of macrophages (flow cytometry). In conclusion, thrombin inhibition by dabigatran promotes an anti-inflammatory phenotype in adipose tissue macrophages in a mouse model of diet-induced obesity and atherosclerosis, probably resulting from a changed expression profile of adipocyte cytokines. These effects might contribute to the known anti-atherosclerotic effects of thrombin inhibition in this model.

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