PCSK9 Promotes Intestinal Overproduction of Triglyceride-Rich Apolipoprotein-B Lipoproteins Through Both LDL-Receptor Dependent and Independent Mechanisms

Study Questions:

How does proprotein convertase subtilisin kexin type 9 (PCSK9) regulate production of triglyceride-rich lipoproteins (TRLs)?

Methods:

The effect of PCSK9 on synthesis and secretion of apolipoproteins was studied in human enterocytes and in low-density lipoprotein receptor (LDLR) deficient mice.

Results:

Addition of PCSK9 to enterocytes increased cellular and secreted apolipoprotein B48 (apoB48) and apoB100 by 40-55% each, whereas deletion of PCSK9 expression reversed this effect. PCSK9 stimulation of apoB was due to an increase in apoB mRNA and enhanced apoB protein stability through both LDLR-dependent and LDLR-independent pathways. PCSK9 decreased LDLR protein and increased apoB stability via activation of microsomal triglyceride transfer protein (MTP). In mice, human PCSK9 at physiologic levels increased intestinal MTP levels and activity regardless of LDLR expression.

Conclusions:

PCSK9 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.

Perspective:

The discovery of PCSK9 as a potent regulator of LDL has led to development of PCSK9 inhibitors that appear to be highly effective in reducing LDL. The mechanism of action of PCSK9 in lipid metabolism is believed to be predominantly due to increased degradation of LDLRs with resultant reduced LDL clearance. However, there are other beneficial effects of PCSK9 inhibition on the lipid profile, and previous studies in mice have demonstrated that the atherogenic effects of PCSK9 are due to both impaired LDL clearance and increased secretion of apoB-containing lipoproteins. This study elucidates the mechanism of these additional properties of PCSK9 and indicates that inhibition of PCSK9 might have the added benefit of inhibiting MTP without the risk of hepatic steatosis seen with other MTP inhibitors.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Lipid Metabolism

Keywords: Lipoproteins, LDL, Lipid Metabolism, Hypertriglyceridemia, Apolipoprotein B-100, Carrier Proteins, Receptors, LDL, RNA, Messenger


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