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

Abstract

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 ( = 0.31, = 0.0002) and production rate ( = 0.24, = 0.008) but not the fractional catabolic rate ( = -0.04, = 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, = 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 and genes was positively associated ( = 0.43, = 0.002). These results support PCSK9 association with intestinal secretion and plasma overaccumulation of TRL apoB-48 in men with IR.

Dilignans with a Chromanol Motif Discovered by Molecular Networking from the Stem Barks of Magnolia obovata and Their Proprotein Convertase Subtilisin/Kexin Type 9 Expression Inhibitory Activity

“…Additionally, downstream target genes of transcriptional factors such as Acyl-CoA synthetase long-chain family 6 (ACSL6), carnitine palmitoyl transferase 1A (CPT1A), and apolipoprotein B (APOB) were upregulated or downregulated. The ACSL6, CPT1A, and APOB genes control fatty acid metabolism, triglyceride metabolism, and catabolism of lipoprotein particles, respectively [ 38 , 39 , 40 ].…”

Associations between insulin-like growth factor binding protein-2 and lipoprotein kinetics in men

“…Circulating lipids were quantified using enzymatic methods and ultracentrifugation as described ( 33 ). Plasma levels of glucose (colorimetry), insulin (electrochemiluminescence), and C-reactive protein (CRP; ELISA) were measured as described ( 34 ). Plasma insulin values were only available for 177 individuals.…”

“…Blood was collected at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 11, and 12 h during the infusion. Isolation and quantification of lipoprotein fractions, apoB-100, apoB-48, and isotopic enrichment determinations were performed exactly as described previously ( 34 , 35 , 36 , 37 ). Kinetics analysis as a function of plasma volume was calculated exactly as described previously ( 34 ).…”

“…Isolation and quantification of lipoprotein fractions, apoB-100, apoB-48, and isotopic enrichment determinations were performed exactly as described previously ( 34 , 35 , 36 , 37 ). Kinetics analysis as a function of plasma volume was calculated exactly as described previously ( 34 ). Kinetics of apoB-48 were calculated in nonfasted participants only.…”

Regulation of PCSK9 Expression and Function: Mechanisms and Therapeutic Implications

“…Conversely, in patients with type-II diabetes mellitus, evolocumab reduces postprandial apoB48 levels even though the effect on postprandial triglyceride levels is not significant, while alirocumab can significantly reduce fasting plasma apoB48 and TG levels and postprandial TG levels (50). Plasma PCSK9 levels are also correlated with plasma apoB48-containing TG-rich lipoproteins in men with insulin resistance (51). However, the impact of PCSK9 on plasma levels of TG-rich lipoproteins, such as VLDL and chylomicrons, is much less than its effect on plasma LDL (52).…”