Proprotein convertase subtilisin kexin type 9 null mice are protected from postprandial triglyceridemia.
OBJECTIVE
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.


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.


CONCLUSIONS
These findings indicate that in addition to its effect on LDL-cholesterol, PCSK9 deficiency might protect against cardiovascular disease by reducing postprandial triglyceridemia.
Le May
Cédric
C
INSERM U915, CHU de Nantes, France.
Kourimate
Sanae
S
Langhi
Cédric
C
Chétiveaux
Maud
M
Jarry
Anne
A
Comera
Christine
C
Collet
Xavier
X
Kuipers
Folkert
F
Krempf
Michel
M
Cariou
Bertrand
B
Costet
Philippe
P
D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism*; D018938:Caco-2 Cells; D002914:Chylomicrons / Q000378:metabolism; D004386:Duodenum / Q000378:metabolism; D020895:Enterocytes / Q000378:metabolism*; D020397:Goblet Cells / Q000378:metabolism; D006801:Humans; D007082:Ileum / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*
D001055:Apolipoproteins B; D002914:Chylomicrons; D014280:Triglycerides; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases