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Updated: Jun 27, 2026
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A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
Function and distribution of circulating human PCSK9 expressed extrahepatically in transgenic mice
Yi Luo1, Laurie Warren, Donghui Xia
1Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton/New London Laboratories, Groton, CT 06340, USA. Yi.Luo@pfi zer.com
Journal of Lipid Research
|December 9, 2008
Summary
Overexpressing proprotein convertase subtilisin/kexin type 9 (PCSK9) in kidneys increased plasma PCSK9, reducing liver LDL receptors and raising cholesterol. PCSK9
Area of Science:
- Biochemistry
- Molecular Biology
- Metabolic Diseases
Background:
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of cholesterol metabolism.
- PCSK9 primarily functions by downregulating liver LDL receptor (LDLR) proteins.
Purpose of the Study:
- To investigate the impact of extrahepatic PCSK9 expression on cholesterol metabolism.
- To determine the tissue specificity of PCSK9-mediated LDLR regulation.
Main Methods:
- Transgenic overexpression of human PCSK9 (hPCSK9) in mouse kidneys.
- Analysis of plasma PCSK9 levels, liver and kidney LDLR protein expression.
- Assessment of plasma lipid profiles (total cholesterol, LDL cholesterol, ApoB) under different dietary conditions.
Main Results:
- Kidney-specific hPCSK9 overexpression led to increased plasma PCSK9 and reduced liver LDLR proteins.
- Liver demonstrated the highest responsiveness to PCSK9-mediated LDLR downregulation compared to kidney and adrenal glands.
- Elevated plasma PCSK9 increased total cholesterol, LDL cholesterol, and ApoB, with diet exacerbating these effects.
- PCSK9 exhibited heterogeneous size distribution in plasma, shifting towards larger complexes with high-fat, high-cholesterol diets.
Conclusions:
- Human PCSK9 secreted from extrahepatic tissues effectively degrades liver LDLR, increasing plasma LDL levels.
- PCSK9-mediated LDLR regulation exhibits significant tissue specificity, with the liver being the most sensitive.
- Dietary factors influence PCSK9 distribution and its impact on cholesterol metabolism.
