Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue

Arterioscler Thromb Vasc Biol. 2011 Apr;31(4):785-91. doi: 10.1161/ATVBAHA.110.220988. Epub 2011 Jan 27.

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.

Methods and 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / enzymology*
  • Adipocytes / pathology
  • Adiposity* / genetics
  • Age Factors
  • Animals
  • Cholesterol / metabolism
  • Female
  • Homeostasis
  • Hydrolysis
  • Hypertrophy
  • Immunohistochemistry
  • Intra-Abdominal Fat / enzymology*
  • Intra-Abdominal Fat / pathology
  • Liver / enzymology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oleic Acid / metabolism
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism*
  • Serine Endopeptidases / blood
  • Serine Endopeptidases / deficiency
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*
  • Sex Factors
  • Triglycerides / metabolism*

Substances

  • Receptors, LDL
  • Triglycerides
  • VLDL receptor
  • Oleic Acid
  • Cholesterol
  • Pcsk9 protein, mouse
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases