PCSK9 Promotes Intestinal Overproduction of Triglyceride-Rich Apolipoprotein-B Lipoproteins Through Both LDL-Receptor Dependent and Independent Mechanisms
Background—Proprotein convertase subtilisin kexin type 9 (PCSK9) promotes the degradation of the low-density lipoprotein receptor (LDLR), and its deficiency in humans results in low plasma LDL-cholesterol and protection against coronary heart disease (CHD). Recent evidence indicates that PCSK9 also modulates the metabolism of triglyceride-rich apolipoprotein B (apoB) lipoproteins (TRL), another important CHD risk factor. Here we studied effects of physiological levels of PCSK9 on intestinal TRL production and elucidated for the first time the cellular and molecular mechanisms involved.
Methods and Results—Treatment of human enterocytes (CaCo-2 cells) with recombinant human PCSK9 (10 µg/mL, 24 hours) increased cellular and secreted apoB48 and apoB100 by 40-55% each (p<0.01 vs. untreated cells), whereas acute deletion of PCSK9 expression reversed this effect. PCSK9 stimulation of apoB was due to: (1) a 1.5-fold increase in apoB mRNA (p<0.01); and (2) enhanced apoB protein stability through both LDLR-dependent and LDLR-independent mechanisms. PCSK9 decreased LDLR protein (p<0.01) and increased cellular apoB stability via activation of microsomal triglyceride transfer protein (MTP). PCSK9 also increased levels of the lipid-generating enzymes FAS, SCD and DGAT2 (p<0.05). In mice, human PCSK9 at physiologic levels increased intestinal MTP levels and activity regardless of LDLR expression.
Conclusions—PCSK9 markedly increases intestinal TRL apoB production through mechanisms mediated in part by transcriptional effects on apoB, MTP and lipogenic genes, and in part by post-transcriptional effects on the LDLR and MTP. These findings indicate that targeted PCSK9-based therapies may also be effective in the management of postprandial hypertriglyceridemia.
- Received October 5, 2013.
- Revision received May 13, 2014.
- Accepted May 16, 2014.