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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:684.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Proprotein Convertase Subtilisin Kexin Type 9 Null Mice Are Protected From Postprandial Triglyceridemia

Cédric Le May; Sanae Kourimate; Cédric Langhi; Maud Chétiveaux; Anne Jarry; Christine Comera; Xavier Collet; Folkert Kuipers; Michel Krempf; Bertrand Cariou; Philippe Costet

From the INSERM U915 (C.L.M., S.K., C.L., M.C., M.K., B.C., P.C.), CHU de Nantes, France; Université de Nantes, EA Biometadys (A.J.), Nantes, France; INSERM U563 (C.C., X.C.), Toulouse, France; the Center for Liver, Digestive, and Metabolic Diseases (F.K.), University of Groningen, The Netherlands; Université de Nantes, l’institut du thorax (M.K., B.C.), Clinique d’Endocrinologie et Nutrition, Nantes, France; the Centre de Recherche en Nutrition Humaine de Nantes (M.K., P.C.), Nantes, France; and INRA UR66 (C.C.), France.

Correspondence to Philippe Costet, INSERM U915, CHU Hôtel Dieu, 3ENORD, 9, Quai Moncousu, 44000, Nantes, France. E-mail philippe.costet{at}univ-nantes.fr

Objectives— Proprotein convertase subtilisin kexin type 9 (PCSK9) is a natural inhibitor of the low-density lipoprotein receptor, and its deficiency in humans results in low plasma LDL-cholesterol and protection against cardiovascular disease. We explored whether PCSK9 expression impacts postprandial triglyceridemia, another important cardiovascular risk factor.

Methods and Results— Real-time PCR and confocal microscopy were used to show that PCSK9 is expressed throughout the entire small intestine and in human enterocytes. On olive oil gavage, PCSK9-deficient mice showed a dramatically decreased postprandial triglyceridemia compared with their wild-type littermates. Lymph analysis revealed that intestinal TG output is not quantitatively modified by PCSK9 deletion. However, PCSK9^–/– mice present with 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 TG-rich 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.

Conclusion— These findings indicate that in addition to its effect on LDL-cholesterol, PCSK9 deficiency might protect against cardiovascular disease by reducing postprandial triglyceridemia.

This study shows that PCSK9 is expressed throughout the entire small intestine and in human enterocytes. In mice, PCSK9 deficiency dramatically reduces postprandial triglyceridemia. This phenotype can be explained by qualitative modifications of intestinal chylomicron production and an enhanced hepatic catabolism.

Key Words: PCSK9 • chylomicron • postprandial • intestine • CaCo-2