Plasma PCSK9 correlates with apoB-48-containing triglyceride-rich lipoprotein production in men with insulin resistance

Intestinal triglyceride (TG)-rich lipoproteins (TRLs) are important in the pathogenesis of atherosclerosis in insulin resistance (IR). We investigated the association of plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations with apoB-48-containing TRL metabolism in 148 men displaying various degrees of IR by measuring in vivo kinetics of TRL apoB-48 during a constant-fed state after a primed-constant infusion of L-[5,5,5-D3]leucine. Plasma PCSK9 concentrations positively correlated with TRL apoB-48 pool size (r = 0.31, P = 0.0002) and production rate (r = 0.24, P = 0.008) but not the fractional catabolic rate (r = −0.04, P = 0.6). Backward stepwise multiple linear regression analysis identified PCSK9 concentrations as a positive predictor of TRL apoB-48 production rate (standard β = +0.20, P = 0.007) independent of BMI, age, T2D/metformin use, dietary fat intake during the kinetic study, and fasting concentrations of TGs, insulin, glucose, LDL cholesterol, or C-reactive protein. We also assessed intestinal expression of key genes involved in chylomicron processing from duodenal samples of 71 men. Expression of PCSK9 and HMG-CoAR genes was positively associated (r = 0.43, P = 0.002). These results support PCSK9 association with intestinal secretion and plasma overaccumulation of TRL apoB-48 in men with IR. Intestinal triglyceride (TG)-rich lipoproteins (TRLs) are important in the pathogenesis of atherosclerosis in insulin resistance (IR). We investigated the association of plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations with apoB-48-containing TRL metabolism in 148 men displaying various degrees of IR by measuring in vivo kinetics of TRL apoB-48 during a constant-fed state after a primed-constant infusion of L-[5,5,5-D3]leucine. Plasma PCSK9 concentrations positively correlated with TRL apoB-48 pool size (r = 0.31, P = 0.0002) and production rate (r = 0.24, P = 0.008) but not the fractional catabolic rate (r = −0.04, P = 0.6). Backward stepwise multiple linear regression analysis identified PCSK9 concentrations as a positive predictor of TRL apoB-48 production rate (standard β = +0.20, P = 0.007) independent of BMI, age, T2D/metformin use, dietary fat intake during the kinetic study, and fasting concentrations of TGs, insulin, glucose, LDL cholesterol, or C-reactive protein. We also assessed intestinal expression of key genes involved in chylomicron processing from duodenal samples of 71 men. Expression of PCSK9 and HMG-CoAR genes was positively associated (r = 0.43, P = 0.002). These results support PCSK9 association with intestinal secretion and plasma overaccumulation of TRL apoB-48 in men with IR. Intestinal triglyceride (TG)-rich lipoproteins (TRLs) are important contributors of postprandial hypertriglyceridemia, a major cardiovascular disease risk factor (1.Nordestgaard B.G. Benn M. Schnohr P. Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women.JAMA. 2007; 298: 299-308Crossref PubMed Scopus (1607) Google Scholar). Although chylomicrons are too large to enter the subendothelial space, once hydrolyzed, cholesterol-rich chylomicron remnants are small enough to penetrate the subendothelial space, and these particles contribute to the formation of foam cells and impair endothelial function (2.Pal S. Semorine K. Watts G.F. Mamo J. Identification of lipoproteins of intestinal origin in human atherosclerotic plaque..Clin. Chem. Lab. Med. 2003; 41: 792-795Crossref PubMed Scopus (83) Google Scholar, 3.Doi H. Kugiyama K. Ohgushi M. Sugiyama S. Matsumura T. Ohta Y. Nakano T. Nakajima K. Yasue H. Remnants of chylomicron and very low density lipoprotein impair endothelium-dependent vasorelaxation.Atherosclerosis. 1998; 137: 341-349Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar). In the last years, the link between insulin resistance (IR) and the overproduction and decreased clearance of intestinally derived apo B-48-containing TRLs was extensively described in humans (4.Hogue J.C. Lamarche B. Tremblay A.J. Bergeron J. Gagne C. Couture P. Evidence of increased secretion of apolipoprotein B-48-containing lipoproteins in subjects with type 2 diabetes.J. Lipid Res. 2007; 48: 1336-1342Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 5.Duez H. Lamarche B. Uffelman K.D. Valero R. Cohn J.S. Lewis G.F. Hyperinsulinemia is associated with increased production rate of intestinal apolipoprotein B-48-containing lipoproteins in humans.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 1357-1363Crossref PubMed Scopus (143) Google Scholar). Therefore, given the atherogenicity of intestinal lipoproteins, identifying mechanisms responsible for their overaccumulation in subjects with IR is of great interest. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a major role in lipoprotein clearance by promoting intracellular lysosomal degradation of hepatic lipoprotein receptors—namely, the LDL the and the M. A. 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PCSK9 is associated with multiple in a large Full Text Full Text PDF PubMed Scopus Google Scholar, M. A. A. R. A. between plasma proprotein convertase subtilisin/kexin type 9 and the of in a Scopus Google PCSK9 to the overaccumulation of apoB-48-containing lipoproteins by their secretion and their clearance in IR the to PCSK9 concentrations TRL apoB-48 metabolism in samples of humans and to in the IR state M. C. T. S. R. R. J. of PCSK9 with lipoprotein metabolism in PubMed Scopus Google Scholar, J. Watts G.F. between proprotein convertase subtilisin/kexin type apolipoprotein and plasma apolipoprotein in a in the postprandial PubMed Scopus Google Scholar). of the was to the association between PCSK9 and TRL metabolism in the between plasma concentrations of PCSK9 and TRL apoB-48 production rate fractional catabolic rate and pool size was in a large of men with various degrees of IR. We plasma PCSK9 concentrations are positively associated with TRL apoB-48 and and associated with TRL apoB-48 We also the association between the intestinal expression of PCSK9 and the expression of key genes involved in and chylomicron We PCSK9 intestinal are positively associated with the intestinal expression of and as intestinal cells PCSK9 a intestinal expression of these genes S. H. J. S. Proprotein convertase type 9 intestinal overproduction of apolipoprotein lipoproteins lipoprotein and PubMed Scopus Google Scholar, A. S. C. S. Couture P. plays a role in and in intestinal Full Text Full Text PDF PubMed Scopus Google Scholar). was a analysis of from subjects in in vivo kinetic in A.J. Lamarche B. J.C. Bergeron J. Gagne C. Couture P. of for plasma apo in with the LDL Full Text Full Text PDF PubMed Scopus Google Scholar, A.J. Lamarche B. Cohn J.S. J.C. Couture P. of the in vivo kinetics of apoB-48 and in men with Thromb. Vasc. Biol. 2006; 26: PubMed Scopus Google Scholar, J.C. 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TRL apoB-48 kinetics a infusion of subjects in a intestinal expression of PCSK9 and key genes involved in and chylomicron metabolism was assessed in duodenal in the fasting PCSK9 concentrations not associated with TRL apoB-48 but independent positive of TRL apoB-48 and intestinal expression of PCSK9 was positively associated with genes involved in and and the of cholesterol-rich lipoproteins PCSK9 is associated with intestinal secretion and plasma overaccumulation of TRL apoB-48 in men displaying various degrees of IR. of of the secretion and the clearance of intestinal TRLs are key to the overaccumulation of these particles in IR the of PCSK9 in the the role of proprotein in lipoprotein metabolism the lysosomal intracellular degradation of PCSK9 and mechanisms in and in PubMed Scopus Google Scholar). In in and a between PCSK9 and intestinal and hepatic lipoprotein secretion S. H. J. S. 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