Abstract 5518: Mice Deficient for Proprotein Convertase Subtilisin Kexin Type 9 are Protected Against Postprandial Lipemia
Introduction. Proprotein convertase subtilisin kexin type 9 (PCSK9) is a natural inhibitor of the low density lipoprotein receptor (LDLR) and its deficiency confers a high level of protection against cardiovascular disease. PCSK9 is well expressed in the liver and the intestine but its precise localization and its role in the digestive tract remain unknown.
Objectives. The aim of this study is to determine PCSK9 distribution and localization in the intestine and examine in mice whether it acts upon postprandial lipemia.
Methods & Results. In mice, we show that PCSK9 mRNA is highly expressed all along the small intestine and colon. Confocal microscopy on human intestines showed that PCSK9 is localized mainly in the enterocyte. Similar to hepatocytes, PCSK9 was induced by statins in polarized Caco-2 cells. Upon olive oil gavage, and in spite of similar fasting triglyceridemia, PCSK9−/− mice have a dramatically decreased postprandial triglyceridemia compared with their wild type littermates (WT) (0.075g/L/h vs 0.2g/L/h, p<0.01). PCSK9 knockouts clear their own chylomicrons faster than chylomicrons from WT (+56%, p<0.001). In vivo kinetic studies using an inhibitor of lipases suggested an intestinal defect. On regular chow diet, PCSK9 knockout mice have increased fecal glycerol contents (+15%). Upon gavage, intestines from knockout mice accumulated less triglycerides. Collection of lymph during the absorption process, by cannulation of the lymph duct, showed reduced apoB48 output in knockout mice, but higher apoB48 to TG ratios. Interestingly, the knockdown of PCSK9 in differentiated Caco-2 cells using SiRNA resulted in lower 35S-apoB secretion. Adenoviral overexpression of PCSK9 led to the opposite result.
Conclusions. Altogether, these data suggest that PCSK9 deficiency might protect against cardiovascular disease not only by affecting the LDLC but also by reducing postprandial triglyceridemia, an important risk factor.