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.

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.

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). Lymph analysis revealed that intestinal TG output is not quantitatively modified by PCSK9 deletion. However, PCSK9-/- mice present a significant reduction of lymphatic apoB secretion compared to PCSK9+/+ mice. Modulating PCSK9 expression in polarized Caco-2 cells confirmed the relationship between PCSK9 and apoB secretion; PCSK9-/- mice consistently secrete larger TGrich lipoprotein than wild-type littermates. Finally, kinetic studies showed that PCSK9 deficient mice have an increased ability to clear chylomicrons compared to wild-type littermates.

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.