The Effect of PCSK9 Loss-of-Function Variants on the Postprandial Lipid and ApoB-Lipoprotein Response.

Context: Proprotein convertase subtilisin kexin 9 (PCSK9) mediates degradation of the low-density lipoprotein receptor (LDLR), thereby increasing plasma low-density lipoprotein cholesterol (LDL-C). Variations in the PCSK9 gene associated with loss of function (LOF) of PCSK9 result in greater expression of hepatic LDLR, lower concentrations of LDL-C, and protection from cardiovascular disease (CVD). Apolipoprotein-B (apoB) remnants also contribute to CVD risk and are similarly cleared by the LDLR.

The anti-adipogenic effect of peripheral blood mononuclear cells is absent with PCSK9 loss-of-function variants.

Objective: To determine the effect of (1) an oral fat load and (2) pro-protein convertase subtilisin/kexin type (PCSK) 9 loss-of-function (LOF) variant status on the ability of peripheral blood mononuclear cells (PBMC) to inhibit human adipogenesis.

Methods: PBMC from subjects with one or more PCSK9 LOF variants versus non-variant controls were compared in the fasting state and after an oral fat load.

Results: Fasting triglyceride (TG) levels were lower in the LOF variant versus non-variant group but rose to the same level after the oral fat load.