Statins and PCSK9 inhibitors dramatically lower plasma LDL levels and dramatically increase LDL receptor number within hepatocyte cell membranes. It seems self-evident that total clearance of LDL particles from plasma and total delivery of cholesterol to the liver must increase in consequence. However, based on the results of stable isotope tracer studies, this analysis demonstrates the contrary to be the case. Statins do not change the production rate of LDL particles. Accordingly, at steady state, the clearance rate cannot change. Because LDL particles contain less cholesterol on statin therapy, the delivery of cholesterol to the liver must, therefore, be reduced. PCSK9 inhibitors reduce the production of LDL particles and this further reduces cholesterol delivery to the liver. With both agents, a larger fraction of a smaller pool is removed per unit time. These findings are inconsistent with the conventional model of cholesterol homeostasis within the liver, but are consistent with a new model of regulation, the multi-channel model, which postulates that different lipoprotein particles enter the hepatocyte by different routes and have different metabolic fates within the hepatocyte. The multi-channel model, but not the conventional model, may explain how statins and PCSK9 inhibitors can produce sustained increases in LDL receptor number.
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May 2017
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Image demonstrates the ultrastructural cortical basement membrane changes in SHRSP brain: accumulation of lipofuscin in pericytes. For further details, see article by Screiber et al in this issue (pages 1001–1013). Image kindly provided by Stefanie Schreiber.
Editorial|
April 19 2017
Statins, PCSK9 inhibitors and cholesterol homeostasis: a view from within the hepatocyte
Allan D. Sniderman;
1Royal Victoria Hospital–McGill University Health Centre 1001, Decarie Boul., Montreal, Quebec, Canada H4A 3J1
Correspondence: Allan D. Sniderman (allansniderman@hotmail.com)
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Robert Scott Kiss;
Robert Scott Kiss
1Royal Victoria Hospital–McGill University Health Centre 1001, Decarie Boul., Montreal, Quebec, Canada H4A 3J1
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Thomas Reid;
Thomas Reid
1Royal Victoria Hospital–McGill University Health Centre 1001, Decarie Boul., Montreal, Quebec, Canada H4A 3J1
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George Thanassoulis;
George Thanassoulis
1Royal Victoria Hospital–McGill University Health Centre 1001, Decarie Boul., Montreal, Quebec, Canada H4A 3J1
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Gerald F. Watts
Gerald F. Watts
2Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, School of Medicine, University of Western Australia, Perth, Australia
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Publisher: Portland Press Ltd
Received:
January 13 2017
Revision Received:
February 21 2017
Accepted:
March 06 2017
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society
2017
Clin Sci (Lond) (2017) 131 (9): 791–797.
Article history
Received:
January 13 2017
Revision Received:
February 21 2017
Accepted:
March 06 2017
Citation
Allan D. Sniderman, Robert Scott Kiss, Thomas Reid, George Thanassoulis, Gerald F. Watts; Statins, PCSK9 inhibitors and cholesterol homeostasis: a view from within the hepatocyte. Clin Sci (Lond) 1 May 2017; 131 (9): 791–797. doi: https://doi.org/10.1042/CS20160872
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