Secreted proprotein convertase subtilisin/kexin type 9 reduces both hepatic and extrahepatic low-density lipoprotein receptors in vivo
| Autor: | Aiming Lin, Yue-Wei Qian, Guoqing Cao, William R. Bensch, Robert J. Schmidt, Robert J. Konrad, Mark C. Kowala, William E. Alborn, Thomas P. Beyer |
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| Rok vydání: | 2008 |
| Předmět: |
Male
medicine.medical_specialty Biophysics Adipose tissue Biology Biochemistry Catalysis Adenoviridae Mice chemistry.chemical_compound Internal medicine medicine Animals Humans Molecular Biology Cholesterol PCSK9 Serine Endopeptidases Cholesterol LDL Cell Biology Proprotein convertase Recombinant Proteins Mice Inbred C57BL Endocrinology Liver Receptors LDL chemistry Low-density lipoprotein Injections Intravenous LDL receptor Kexin lipids (amino acids peptides and proteins) Proprotein Convertases Proprotein Convertase 9 Lipoprotein |
| Zdroj: | Biochemical and Biophysical Research Communications. 370:634-640 |
| ISSN: | 0006-291X |
| Popis: | Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that is known to reduce hepatic low-density lipoprotein receptor (LDLR) levels and increase plasma LDL cholesterol. It is not clear, however, whether secreted PCSK9 degrades extrahepatic LDLRs. We present evidence that recombinant PCSK9, either injected intravenously into or expressed in the liver of C57BL/6 mice, significantly reduced LDLR levels in multiple extrahepatic tissues. During the initial characterization, we found that injected human recombinant PCSK9 at 30 microg/mouse had a half-life of 15 min in serum in mice. Hepatic LDLR levels were reduced within 30min and the degradation of hepatic LDLR reached the maximum 2h after the initial protein injection. Endocytosis of PCSK9 in liver occurred within 5min of protein injection and internalized PCSK9 was only barely detectable within 1h. When extrahepatic LDLRs were examined by Western blotting analysis, we found significant reductions of LDLRs in multiple extrahepatic tissues including lung, adipose and kidney along with the more dramatic reduction of LDLRs in liver. These studies were further extended using adenoviral expression of human PCSK9 in C57BL/6 mice to demonstrate that PCSK9 produced in liver impacted extrahepatic tissue LDLR levels as well. Taken together, our studies indicate that secreted PCSK9 can potentially impact extrahepatic tissue cholesterol homeostasis by regulating extrahepatic tissue LDLR levels. |
| Databáze: | OpenAIRE |
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