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Circulation. 2014 Jul 29;130(5):431-41. doi: 10.1161/CIRCULATIONAHA.113.006720. Epub 2014 May 23.

Proprotein convertase subtilisin kexin type 9 promotes intestinal overproduction of triglyceride-rich apolipoprotein B lipoproteins through both low-density lipoprotein receptor-dependent and -independent mechanisms.

Author information

  • 1From the Department of Pharmacology, Dalhousie University, Halifax, NS, and Saint John, NB, Canada (S.R.); Department of Medicine, Section of Cardiovascular Disease Prevention, Vanderbilt University, Nashville, TN (H.T., M.F.L., J.H., I.G., S.F.); Oregon Health and Science University, Portland (H.T., I.G.); and Department of Biostatistics, Faculty of Medicine, University of Toronto and Cancer Care Ontario, Toronto, ON, Canada (P.E.B.). shirya.rashid@Dal.ca.
  • 2From the Department of Pharmacology, Dalhousie University, Halifax, NS, and Saint John, NB, Canada (S.R.); Department of Medicine, Section of Cardiovascular Disease Prevention, Vanderbilt University, Nashville, TN (H.T., M.F.L., J.H., I.G., S.F.); Oregon Health and Science University, Portland (H.T., I.G.); and Department of Biostatistics, Faculty of Medicine, University of Toronto and Cancer Care Ontario, Toronto, ON, Canada (P.E.B.).

Erratum in

Abstract

BACKGROUND:

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. Recent evidence indicates that PCSK9 also modulates the metabolism of triglyceride-rich apolipoprotein B (apoB) lipoproteins, another important coronary heart disease risk factor. Here, we studied the effects of physiological levels of PCSK9 on intestinal triglyceride-rich apoB lipoprotein 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 for 24 hours) increased cellular and secreted apoB48 and apoB100 by 40% to 55% each (P<0.01 versus untreated cells), whereas short-term deletion of PCSK9 expression reversed this effect. PCSK9 stimulation of apoB was due to a 1.5-fold increase in apoB mRNA (P<0.01) and to 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. PCSK9 also increased levels of the lipid-generating enzymes FAS, SCD, and DGAT2 (P<0.05). In mice, human PCSK9 at physiological levels increased intestinal microsomal triglyceride transfer protein levels and activity regardless of LDLR expression.

CONCLUSIONS:

PCSK9 markedly increases intestinal triglyceride-rich apoB production through mechanisms mediated in part by transcriptional effects on apoB, microsomal triglyceride transfer protein, and lipogenic genes and in part by posttranscriptional effects on the LDLR and microsomal triglyceride transfer protein. These findings indicate that targeted PCSK9-based therapies may also be effective in the management of postprandial hypertriglyceridemia.

© 2014 American Heart Association, Inc.

KEYWORDS:

apolipoproteins; lipids; molecular biology; pathophysiology; receptors, lipoprotein; risk factors

PMID:
25070550
[PubMed - indexed for MEDLINE]
PMCID:
PMC4115295
Free PMC Article
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