Atherosclerosis 236 (2014) 321e326

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PCSK9 levels in abdominally obese men: Association with cardiometabolic risk profile and effects of a one-year lifestyle modification program ras a, Benoit J. Arsenault a, b, *, Emilie Pelletier-Beaumont a, c, Natalie Alme a, c a, d e s a, c , Jean Bergeron , Jean-Pierre Despre Angelo Tremblay , Paul Poirier Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Qu ebec, Canada Department of Medicine, Faculty of Medicine, Universit e Laval, Qu ebec, Canada Department of Kinesiology, Faculty of Medicine, Universit e Laval, Qu ebec, Canada d Faculty of Pharmacy, Universit e Laval, Qu ebec, Canada e Lipid Research Centre, CHU de Qu ebec Research Centre, Qu ebec, Canada a

b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 27 May 2014 Received in revised form 1 July 2014 Accepted 13 July 2014 Available online 26 July 2014

Objectives: Studies performed in rodents have suggested a role for proprotein convertase subtilisin/kexin type 9 (PCSK9) in insulin resistance and impaired body fat distribution. Our objective was to examine the relationships between markers of adiposity and insulin resistance and plasma PCSK9 levels in humans. In addition, we explored the effect of a one-year lifestyle modification program on plasma PCSK9 levels in abdominally obese, dyslipidemic men. Methods: Plasma PCSK9 levels were measured by ELISA in 175 abdominally obese, dyslipidemic sedentary men. Of these abdominally obese men, 117 non-diabetic individuals completed a one-year lifestyle modification program aiming at increasing cardiorespiratory fitness levels and improving nutritional quality. Results: We found no association between plasma PCSK9 levels and body mass index, waist circumference, fat and fat-free mass, or visceral and subcutaneous adipose tissue measured by computed tomography. Compared to men with the lowest PCSK9 levels (bottom tertile), those with the highest PCSK9 levels (top tertile) had the most detrimental lipoprotein-lipid profile including lower LDL particle size (253.6 ± 4.0 vs. 251.6 ± 4.0 Å, p < 0.05) and higher apolipoprotein C-III levels (36.8 ± 10.6 vs. 32.3 ± 32.3, p < 0.05). These men were also characterized by higher HOMA-IR indices (6.78 ± 3.01 vs. 5.54 ± 2.91, p < 0.05). After one year, study participants lost on average 6.7 ± 4.6 kg (p < 0.0001). Plasma PCSK9 decreased by 9.2 ± 53.7 ng/ml (3.8%, p ¼ 0.07). Conclusions: Plasma PCSK9 levels are not associated with body fat distribution indices, modestly associated with markers of insulin resistance and LDL particle size and are slightly affected by a lifestyle modification program in abdominally obese men. © 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: PCSK9 Physical activity Nutrition Obesity Insulin resistance

1. Introduction In 2003, Abifadel and colleagues performed a genetic linkage association study in French families with abnormally elevated levels of low-density lipoprotein (LDL) cholesterol and identified the gene encoding for proprotein convertase subtilisin/kexin type 9

* Corresponding author. Centre de recherche de l'Institut universitaire de carbec, Y-2110, Pavillon Marguerite D'Youville, 2725 diologie et de pneumologie de Que bec, QC G1V 4G5, Canada. Tel.: þ1 418 656 8711x3498. chemin Ste-Foy, Que E-mail address: [email protected] (B.J. Arsenault). http://dx.doi.org/10.1016/j.atherosclerosis.2014.07.010 0021-9150/© 2014 Elsevier Ireland Ltd. All rights reserved.

(PCSK9) as a susceptibility locus for familial hypercholesterolemia (FH) [1]. In the following years, several groups around the world confirmed this finding and it is nowadays well accepted that approximately 2% of FH cases may be attributable to gain-offunction mutations at the PCSK9 locus [2]. The role of PCSK9 on coronary artery disease (CAD) risk has been documented by genome-wide association and Mendelian randomization studies, which have confirmed that individuals carrying a common singlenucleotide polymorphism (SNP) at the PCSK9 locus were simultaneously characterized by low LDL cholesterol levels and a decreased CAD risk [3e5]. Several investigations using the Pcsk9/ mouse model have been performed to better understand the mechanisms

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that linked PCSK9 with LDL cholesterol levels and CAD risk. These studies confirmed that PCSK9 is a secreted protein which binds with high affinity to the epidermal growth factor like domain-A of the LDL receptor (LDLR) at the surface of hepatocytes and other cell types, thereby flagging the LDLR for lysosomal degradation thus halting its recycling at the cell surface [6,7]. Reduced LDLR concentration at the surface of the hepatocyte hampers LDL particle uptake and is thereby associated with high LDL cholesterol levels and increased atherosclerosis burden, as suggested by a recent study using the Pcsk9/ mouse [8]. Recent investigations on Pcsk9/ mice also lead to peculiar findings. For instance, a recent study documented that Pcsk9/ mice had 80% more visceral fat compared to wild-type mice and suggested that by targeting the very low-density lipoprotein receptor (VLDLR) in adipocytes, PCSK9 may be an important regulatory factor of visceral adipocytes maturation [9]. Another study using the same model showed that Pcsk9/ mice were characterized by pancreatic islets that exhibited signs of malformation, apoptosis and inflammation leading to a severely glucose intolerant state [10]. Another study however, did not find any features of insulin resistance in Pcsk9/ mice. [11] Although some studies have shown that plasma PCSK9 may be associated positively with plasma insulin levels in humans, most studies conducted on the topic had cross-sectional designs [12,13]. Additionally, there have been no studies to our knowledge on the impact of PCSK9 levels on body fat distribution (or vice-versa) in humans. Our objective was to determine the association between plasma PCSK9 levels and markers of lipoprotein-lipid metabolism, glucoseinsulin homeostasis, body fat distribution, inflammation and cardiorespiratory fitness in abdominally obese men. We also aimed at documenting the directionality of these associations by studying the impact of a lifestyle modification program that significantly improved insulin sensitivity, fitness levels and adiposity on plasma PCSK9 levels in these men. 2. Materials and methods 2.1. Study participants A sample of 175 men, aged between 30 and 65 years, were bec City metropolitan area. recruited through the media in the Que Participants had to be sedentary, which was defined as less than 30 min of continuous and vigorous physical activity per week performed over the past two months and to have an elevated waist circumference (90 cm) combined with the presence of high triglycerides (1.69 mmol/L) and/or low HDL cholesterol levels (

PCSK9 levels in abdominally obese men: association with cardiometabolic risk profile and effects of a one-year lifestyle modification program.

Studies performed in rodents have suggested a role for proprotein convertase subtilisin/kexin type 9 (PCSK9) in insulin resistance and impaired body f...
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