Circulating Proprotein Convertase Subtilisin Kexin Type 9 Has a Diurnal Rhythm Synchronous With Cholesterol Synthesis and Is Reduced by Fasting in Humans
Authors:
- Guoqing CaoGCGuoqing Cao
- Lars StåhLeLSLars StåhLe
- Beatrice G. SjöbErgBSBeatrice G. SjöbErg
- Jason S. TrouttJTJason S. Troutt
- Robert J. KonradRKRobert J. Konrad
- Cecilia GälManCGCecilia GälMan
- HåkAn WallénHWHåkAn Wallén
- Mats ErikssonMEMats Eriksson
- IngiälD HafströmIHIngiälD Hafström
- Suzanne LindSLSuzanne Lind
- Maria DahlinMDMaria Dahlin
- 1 December 2010
- journal article
- research article
- Published by Wolters Kluwer Health in Arteriosclerosis, Thrombosis, and Vascular Biology
- Vol. 30 (12) , 2666-2672
Abstract
Objective— To gain insight into the function of proprotein convertase subtilisin kexin type 9 (PCSK9) in humans by establishing whether circulating levels are influenced by diurnal, dietary, and hormonal changes. Methods and Results— We monitored circulating PCSK9 in a set of dynamic human experiments and could show that serum PCSK9 levels display a diurnal rhythm that closely parallels that of cholesterol synthesis, measured as serum lathosterol. In contrast to these marked diurnal changes in cholesterol metabolism, serum low-density lipoprotein (LDL) cholesterol levels remained stable during the diurnal cycle. Depletion of liver cholesterol by treatment with the bile acid–binding resin, cholestyramine, abolished the diurnal rhythms of both PCSK9 and lathosterol. Fasting (>18 hours) strongly reduced circulating PCSK9 and lathosterol levels, whereas serum LDL levels remained unchanged. Growth hormone, known to be increased during fasting in humans, reduced circulating PCSK9 in parallel to LDL cholesterol levels. Conclusion— Throughout the day, and in response to fasting and cholesterol depletion, circulating PCSK9 displays marked variation, presumably related to oscillations in hepatic cholesterol that modify its activity in parallel with cholesterol synthesis. In addition to this sterol-mediated regulation, additional effects on LDL receptors may be mediated by hormones directly influencing PCSK9.Keywords
This publication has 40 references indexed in Scilit:
- Fenofibrate treatment increases human serum proprotein convertase subtilisin kexin type 9 levelsJournal of Lipid Research, 2010
- A new method for measurement of total plasma PCSK9: clinical applicationsJournal of Lipid Research, 2010
- Inhibition of PCSK9: A powerful weapon for achieving ideal LDL cholesterol levelsProceedings of the National Academy of Sciences, 2009
- PCSK9: a convertase that coordinates LDL catabolismJournal of Lipid Research, 2009
- Switch-like Control of SREBP-2 Transport Triggered by Small Changes in ER Cholesterol: A Delicate BalanceCell Metabolism, 2008
- Sequence Variations inPCSK9,Low LDL, and Protection against Coronary Heart DiseaseNew England Journal of Medicine, 2006
- Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9Proceedings of the National Academy of Sciences, 2005
- Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genesProceedings of the National Academy of Sciences, 2003
- Mutations in PCSK9 cause autosomal dominant hypercholesterolemiaNature Genetics, 2003
- The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): Liver regeneration and neuronal differentiationProceedings of the National Academy of Sciences, 2003