Amiodarone disrupts cholesterol biosynthesis pathway and causes accumulation of circulating desmosterol by inhibiting 24-dehydrocholesterol reductase

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Simonen , P , Li , S , Chua , N K , Lampi , A-M , Piironen , V , Lommi , J , Sinisalo , J , Brown , A J , Ikonen , E & Gylling , H 2020 , ' Amiodarone disrupts cholesterol biosynthesis pathway and causes accumulation of circulating desmosterol by inhibiting 24-dehydrocholesterol reductase ' , Journal of Internal Medicine , vol. 288 , no. 5 , pp. 560-569 . https://doi.org/10.1111/joim.13095

Title: Amiodarone disrupts cholesterol biosynthesis pathway and causes accumulation of circulating desmosterol by inhibiting 24-dehydrocholesterol reductase
Author: Simonen, P.; Li, S.; Chua, N. K.; Lampi, A-M; Piironen, V.; Lommi, J.; Sinisalo, J.; Brown, A. J.; Ikonen, E.; Gylling, H.
Contributor organization: Clinicum
HUS Heart and Lung Center
Kardiologian yksikkö
University of Helsinki
Helsinki University Hospital Area
STEMM - Stem Cells and Metabolism Research Program
Faculty of Medicine
Research Programs Unit
Department of Food and Nutrition
Food quality and safety: lipids, vitamins and other bioactive compounds
Food Sciences
Helsinki One Health (HOH)
Department of Medicine
Lipid Trafficking Lab
Department of Anatomy
Date: 2020-11
Language: eng
Number of pages: 10
Belongs to series: Journal of Internal Medicine
ISSN: 0954-6820
DOI: https://doi.org/10.1111/joim.13095
URI: http://hdl.handle.net/10138/320828
Abstract: Background We have earlier reported that amiodarone, a potent and commonly used antiarrhythmic drug increases serum desmosterol, the last precursor of cholesterol, in 20 cardiac patients by an unknown mechanism. Objective Here, we extended our study to a large number of cardiac patients of heterogeneous diagnoses, evaluated the effects of combining amiodarone and statins (inhibitors of cholesterol synthesis at the rate-limiting step of hydroxy-methyl-glutaryl CoA reductase) on desmosterol levels and investigated the mechanism(s) by which amiodarone interferes with the metabolism of desmosterol using in vitro studies. Methods and Results We report in a clinical case-control setting of 236 cardiac patients (126 with and 110 without amiodarone treatment) that amiodarone medication is accompanied by a robust increase in serum desmosterol levels independently of gender, age, body mass index, cardiac and other diseases, and the use of statins. Lipid analyses in patient samples taken before and after initiation of amiodarone therapy showed a systematic increase of desmosterol upon drug administration, strongly arguing for a direct causal link between amiodarone and desmosterol accumulation. Mechanistically, we found that amiodarone resulted in desmosterol accumulation in cultured human cells and that the compound directly inhibited the 24-dehydrocholesterol reductase (DHCR24) enzyme activity. Conclusion These novel findings demonstrate that amiodarone blocks the cholesterol synthesis pathway by inhibiting DHCR24, causing a robust accumulation of cellular desmosterol in cells and in the sera of amiodarone-treated patients. It is conceivable that the antiarrhythmic potential and side effects of amiodarone may in part result from inhibition of the cholesterol synthesis pathway.
Subject: amiodarone
desmosterol
DHCR24
cholesterol biosynthesis
cholesterol absorption
SERUM
METABOLISM
ABSORPTION
EXPRESSION
CATARACT
RECEPTOR
STEROLS
MARKERS
GENE
3121 General medicine, internal medicine and other clinical medicine
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: acceptedVersion


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