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This version published online on June 22, 2006
Endocrinology, doi:10.1210/en.2006-0098
A more recent version of this article appeared on October 1, 2006
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Submitted on January 24, 2006
Accepted on June 15, 2006

Fasting Induces Hyperlipidemia in Mice Overexpressing PCSK9: Lack of Modulation of VLDL Hepatic Output by the LDLr

Gilles Lambert*, Anne-Laure Jarnoux, Thierry Pineau, Olivier Pape, Maud Chetiveaux, Christian Laboisse, Michel Krempf, and Philippe Costet

(GL, ALJ, OP, MC, CL, MK, PC) Université de Nantes, UFR de médecine, Nantes, France; Inserm, U539, Nantes, France; CHU Hôtel-Dieu, Nantes, France.; (TP) Laboratoire de pharmacologie et toxicologie, INRA, Toulouse, France

* To whom correspondence should be addressed. E-mail: gilles.lambert{at}univ-nantes.fr.

Several PCSK9 mutations lead to familial hypercholesterolemia (FH) by virtue of its role as a negative modulator of the LDL receptor (LDLr). Here, we uncover that upon dietary challenge, the down regulation of the LDLr is also a key mechanism by which PCSK9 modulates the hepatic production of apolipoprotein (apo) B containing lipoproteins. Thus, adenoviral mediated overexpression of PCSK9 in 24-hour fasted mice results in massive hyperlipaemia, due to a striking increase in very low density lipoproteins (VLDL) triglycerides (TG) and apoB100 hepatic output. Similar studies in LDLr (-/-) mice demonstrate that PCSK9 mediated alteration of VLDL output in the fasted state requires the LDLr. This increased production of VLDL was associated with a concomitant reduction of intrahepatic lipid stores as well as a lack of down-regulation of Peroxisome Proliferator Activated Receptor (PPAR) {alpha} activity and target genes expression. Finally we show that PCSK9 hepatic expression is inhibited by the hypotriglyceridemic PPAR{alpha} agonist fenofibrate. In summary, the negative modulation of LDLr expression by PCSK9, that decreases plasma LDL clearance, also promotes an overproduction of nascent VLDL in vivo upon fasting.




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