title: Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue.
abstract: OBJECTIVE
  Proprotein convertase subtilisin/kexin 9 (PCSK9) promotes the degradation of the low-density lipoprotein receptor (LDLR), and its gene is the third locus implicated in familial hypercholesterolemia. Herein, we investigated the role of PCSK9 in adipose tissue metabolism.
  
  
  RESULTS
  At 6 months of age, Pcsk9(-/-) mice accumulated ≈80% more visceral adipose tissue than wild-type mice. This was associated with adipocyte hypertrophy and increased in vivo fatty acid uptake and ex vivo triglyceride synthesis. Moreover, adipocyte hypertrophy was also observed in Pcsk9(-/-) Ldlr(-/-) mice, indicating that the LDLR is not implicated. Rather, we show here by immunohistochemistry that Pcsk9(-/-) males and females exhibit 4- and ≈ 40-fold higher cell surface levels of very-low-density lipoprotein receptor (VLDLR) in perigonadal depots, respectively. Expression of PCSK9 in the liver of Pcsk9(-/-) females reestablished both circulating PCSK9 and normal VLDLR levels. In contrast, specific inactivation of PCSK9 in the liver of wild-type females led to ≈ 50-fold higher levels of perigonadal VLDLR.
  
  
  CONCLUSIONS
  In vivo, endogenous PCSK9 regulates VLDLR protein levels in adipose tissue. This regulation is achieved by circulating PCSK9 that originates entirely in the liver. PCSK9 is thus pivotal in fat metabolism: it maintains high circulating cholesterol levels via hepatic LDLR degradation, but it also limits visceral adipogenesis likely via adipose VLDLR regulation.
authors.affiliation: Laboratory of Biochemical Neuroendocrinology, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Roubtsova
authors.forename: Mercedes Nancy
authors.initials: MN
authors.lastname: Munkonda
authors.forename: Zuhier
authors.initials: Z
authors.lastname: Awan
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Marcinkiewicz
authors.forename: Ann
authors.initials: A
authors.lastname: Chamberland
authors.forename: Claude
authors.initials: C
authors.lastname: Lazure
authors.forename: Katherine
authors.initials: K
authors.lastname: Cianflone
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
authors.forename: Annik
authors.initials: A
authors.lastname: Prat
mesh_terms: D017667:Adipocytes / Q000201:enzymology* / Q000473:pathology; D050154:Adiposity / Q000235:genetics; D000367:Age Factors; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D006706:Homeostasis; D006868:Hydrolysis; D006984:Hypertrophy; D007150:Immunohistochemistry; D050152:Intra-Abdominal Fat / Q000201:enzymology* / Q000473:pathology; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019301:Oleic Acid / Q000378:metabolism; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012737:Sex Factors; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D011973:Receptors, LDL; D014280:Triglycerides; C036053:VLDL receptor; D019301:Oleic Acid; D002784:Cholesterol; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases