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Circulating Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Regulates VLDLR Protein and Triglyceride Accumulation in Visceral Adipose Tissue
- Source :
- Arteriosclerosis, Thrombosis, and Vascular Biology. 31:785-791
- Publication Year :
- 2011
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2011.
-
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. Conclusion— 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.
- Subjects :
- Male
medicine.medical_specialty
Adipose tissue
VLDL receptor
Intra-Abdominal Fat
Biology
Mice
Sex Factors
Internal medicine
Adipocytes
medicine
Animals
Homeostasis
Triglycerides
Adiposity
Mice, Knockout
Hydrolysis
PCSK9
Serine Endopeptidases
Age Factors
Hypertrophy
Immunohistochemistry
Mice, Inbred C57BL
Cholesterol
Endocrinology
Liver
Receptors, LDL
Adipogenesis
LDL receptor
Kexin
Female
Proprotein Convertases
Proprotein Convertase 9
Adipocyte hypertrophy
Cardiology and Cardiovascular Medicine
Oleic Acid
Lipoprotein
Subjects
Details
- ISSN :
- 15244636 and 10795642
- Volume :
- 31
- Database :
- OpenAIRE
- Journal :
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Accession number :
- edsair.doi.dedup.....55406a375277f1591bc02824722063e9