Abstract 10066: Physiological Levels of PCSK9 Promote Hepatic and Intestinal Overproduction of Apolipoprotein-B Lipoproteins through LDL-Receptor Dependent and Independent Mechanisms
Background and Rationale: Proprotein convertase subtilisin kexin type 9 (PCSK9) promotes the degradation of the low-density lipoprotein (LDL) receptor (LDLR), and its deficiency in humans results in low plasma LDL-cholesterol and protection against coronary heart disease (CHD). Recent evidence indicates that, at supraphysiological levels, PCSK9 also modulates the metabolism of triglyceride-rich apolipoprotein B (apoB) lipoproteins (TRL), another important CHD risk factor. Here we studied the effects of physiological levels of PCSK9 on hepatic and intestinal TRL production and elucidate the cellular and molecular mechanisms involved.
Results: Treatment of human enterocytes (optimally polarized CaCo-2 cells) with physiological levels of PCSK9 (10 μg/mL, 24 hours) produced a significant 40-55% increase in the cellular expression and secretion of both apoB48 and apoB100 (p<0.01 for all vs. untreated cells). The PCSK9-induced elevation in apoB was due to: (1) a 1.5-fold increase in apoB mRNA expression (p<0.01 vs. control cells); (2) enhanced apoB stability through both LDLR-dependent and LDLR-independent mechanisms. As expected, PCSK9 significantly decreased LDLR protein levels (p<0.01). Additionally, PCSK9 also significantly increased expression and activity (p<0.05 and p<0.01, respectively) of microsomal triglyceride transfer protein (MTP), the rate-limiting protein in apoB stability and assembly into TRL. In addition to increasing apoB synthesis, PCSK9 also increased the expression of NPC1L1, a critical mediator of cholesterol absorption into enterocytes, and of SCD and DGAT1, enzymes involved in intracellular TRL lipid synthesis (p<0.05).
In mice, physiological levels of PCSK9 expression increased TRL secretion and hepatic MTP levels, regardless of LDLR expression.
Conclusions: Our results show that PCSK9 at concentrations observed in healthy humans produced marked increases in hepatic and intestinal TRL apoB synthesis and secretion, partly mediated by newly identified PCSK9 intracellular targets - MTP and NPC1L1. These findings suggest that targeted PCSK9-based therapies may be effective in the management of postprandial hypertriglyceridemia.
- © 2013 by American Heart Association, Inc.