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.