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Journal of Lipid Research, Vol. 50, 938-944, May 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

The thyromimetic T-0681 protects from atherosclerosis

Ivan Tancevski^1,*, Andreas Wehinger, Egon Demetz^*, Julia Hoefer^*, Philipp Eller^*, Eva Huber^*, Ursula Stanzl^*, Kristina Duwensee^*, Kristina Auer^*, Wilfried Schgoer^*, Volker Kuhn, Catherine Fievet^**, Frans Stellaard, Mats Rudling, Bernhard Foeger, Josef R. Patsch^* and Andreas Ritsch^*

^* Department of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria
Department of Surgery, Innsbruck Medical University, Innsbruck, Austria
Department of Internal Medicine, Landeskrankenhaus Bregenz, Bregenz, Austria
^** Département d'Athérosclérose, Institut Pasteur de Lille, Lille Cedex, France
Laboratory of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands
Department for Endocrinology, Metabolism, and Diabetes, Molecular Nutrition Unit, and Departments of Medicine and Biosciences and Nutrition, Karolinska Institutet, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden

This work was supported by the Hans and Blanca Moser Stiftung (No. 61-1994/95 to I.T.), by the Medizinische Forschungsfoerderung Innsbruck (No. 4316 to I.T.), by the Jubiläumsfond der Oesterreichischen Nationalbank (No. 12156 to I.T. and A.R.), and by the Fonds zur Foerderung der wissenschaftlichen Forschung (P19999-B05 to A.R.).

Published, JLR Papers in Press, December 22, 2008.

¹ To whom correspondence should be addressed. e-mail: ivan.tancevski{at}i-med.ac.at

This report describes studies in hyperlipidemic New Zealand White (NZW) rabbits investigating the impact of the liver-selective thyromimetic T-0681 on lipoprotein metabolism and the development of atherosclerosis. Prolonged treatment with T-0681 increased the hepatic expression of both LDL receptor and scavenger receptor class B, type I without affecting cholesteryl ester transfer protein activity. Upregulation of hepatic lipoprotein receptors was accompanied by a marked decrease of apolipoprotein B-containing lipoproteins, reflected by a 60% reduction of plasma cholesterol and a >70% reduction of plasma triglyceride levels. Most importantly, T-0681 reduced the development of atherosclerosis by 80% in NZW rabbits on high-cholesterol chow. Our data suggest that liver-selective thyromimetics, such as T-0681, may prove to be useful therapeutic agents against the development of atherosclerosis in humans.

Supplementary key words liver-selective thyromimetic • low density lipoprotein receptor • scavenger receptor class B, type I • potential side effects

Abbreviations: ABCA1, adenosine 5'-triphosphate-binding cassette transporter 1; AcLDL, acetylated low density lipoprotein; ALT, alanine-aminotransferase; apoB, apolipoprotein B; AST, aspartate-aminotransferase; CETP, cholesteryl ester transfer protein; CYP7A1, cholesterol 7 -hydroxylase; FPLC, fast-protein liquid chromatography; HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; LDL-C, low density lipoprotein cholesterol; LDLr, low density lipoprotein receptor; NZW, New Zealand White; RCT, reverse cholesterol transport; SR-BI, scavenger receptor class B, type I; T₃, 3,3',5'-triiodo-_L-thyronine; T₄, 3,5,3',5'-tetraiodothyronine; TH, thyroid hormone; VLDL-C, very low density lipoprotein cholesterol

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