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Fasting Induces Hyperlipidemia in Mice Overexpressing Proprotein Convertase Subtilisin Kexin Type 9: Lack of Modulation of Very-Low-Density Lipoprotein Hepatic Output by the Low-Density Lipoprotein Receptor

Université de Nantes (G.L., A.-L.J., O.P., M.C., C.L., M.K., P.C.) , UFR de Médecine; Institut de la Santé et de la Recherche Médicale, Unité 539; Centre Hospitalier Universitaire Hôtel-Dieu, 44093 Nantes, France; and Laboratoire de Pharmacologie et Toxicologie (T.P.), Institut National de la Recherche Agronomique, 31000 Toulouse, France

Address all correspondence and requests for reprints to: Gilles Lambert, Institut National de la Santé et de la Recherche Médicale, Unité 539, Centre Hospitalier Universitaire Hôtel Dieu, 3eme étage Nord, 1 Place Alexis Ricordeau, 44093 Nantes cedex 1, France. E mail: gilles.lambert{at}univ-nantes.fr.

Several proprotein convertase subtilisin kexin type 9 (PCSK9) mutations lead to familial hypercholesterolemia by virtue of its role as a negative modulator of the low-density lipoprotein 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-B-containing lipoproteins. Thus, adenoviral-mediated overexpression of PCSK9 in 24-h fasted mice results in massive hyperlipidemia, due to a striking increase in very-low-density lipoprotein (VLDL) triglycerides and apolipoprotein B100 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- activity and target genes expression. Finally, we show that PCSK9 hepatic expression is inhibited by the hypotriglyceridemic peroxisome proliferator-activated receptor- agonist fenofibrate. In summary, the negative modulation of LDLr expression by PCSK9, which decreases plasma LDL clearance, also promotes an overproduction of nascent VLDL in vivo upon fasting.

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