title: 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.
abstract: 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-alpha activity and target genes expression. Finally, we show that PCSK9 hepatic expression is inhibited by the hypotriglyceridemic peroxisome proliferator-activated receptor-alpha 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.
authors.affiliation: Université de Nantes, UFR de Médecine, Institut National de la Santé et de la Recherche Médicale, Unité 539, Centre Hospitalier Universitaire Hôtel Dieu, 44093 Nantes, France. gilles.lambert@univ-nantes.fr
authors.forename: Gilles
authors.initials: G
authors.lastname: Lambert
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Jarnoux
authors.forename: Thierry
authors.initials: T
authors.lastname: Pineau
authors.forename: Olivier
authors.initials: O
authors.lastname: Pape
authors.forename: Maud
authors.initials: M
authors.lastname: Chetiveaux
authors.forename: Christian
authors.initials: C
authors.lastname: Laboisse
authors.forename: Michel
authors.initials: M
authors.lastname: Krempf
authors.forename: Philippe
authors.initials: P
authors.lastname: Costet
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D015153:Blotting, Western; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D005215:Fasting / Q000502:physiology*; D005822:Genetic Vectors; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000235:genetics; D006949:Hyperlipidemias / Q000209:etiology*; D015228:Hypertriglyceridemia / Q000097:blood / Q000235:genetics; D008049:Lipase / Q000097:blood; D008055:Lipids / Q000097:blood; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000378:metabolism; D047493:PPAR alpha / Q000502:physiology; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011973:Receptors, LDL / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000502:physiology*
chemical_list: D001055:Apolipoproteins B; D018076:DNA, Complementary; D008055:Lipids; D008079:Lipoproteins, VLDL; D047493:PPAR alpha; D011973:Receptors, LDL; D008049:Lipase; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases