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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.

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.
AuthorsGilles Lambert, Anne-Laure Jarnoux, Thierry Pineau, Olivier Pape, Maud Chetiveaux, Christian Laboisse, Michel Krempf, Philippe Costet
JournalEndocrinology (Endocrinology) Vol. 147 Issue 10 Pg. 4985-95 (Oct 2006) ISSN: 0013-7227 [Print] United States
PMID16794006 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Apolipoproteins B
  • DNA, Complementary
  • Lipids
  • Lipoproteins, VLDL
  • PPAR alpha
  • Receptors, LDL
  • Lipase
  • Pcsk9 protein, mouse
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases
Topics
  • Adenoviridae (genetics)
  • Animals
  • Apolipoproteins B (metabolism)
  • Blotting, Western
  • DNA, Complementary (biosynthesis, genetics)
  • Fasting (physiology)
  • Genetic Vectors
  • Humans
  • Hypercholesterolemia (blood, genetics)
  • Hyperlipidemias (etiology)
  • Hypertriglyceridemia (blood, genetics)
  • Lipase (blood)
  • Lipids (blood)
  • Lipoproteins, VLDL (metabolism)
  • Liver (metabolism)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microsomes, Liver (metabolism)
  • PPAR alpha (physiology)
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Receptors, LDL (metabolism)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serine Endopeptidases (biosynthesis, physiology)

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