The thyromimetic T-0681 protects from atherosclerosis

Ivan Tancevski,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,Andreas Ritsch

doi:10.1194/jlr.m800553-jlr200

Abstract

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.

Highlights

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
We used the model of hyperlipidemic NZW rabbits to investigate the influence of a liver-selective thyromimetic for potential use as a therapeutic antiatherosclerotic agent
36 nmoles/kg/day T-0681 was found to reduce plasma levels of both VLDL-C and low density lipoprotein cholesterol (LDL-C), which could be attributed to the induction of hepatic LDL receptor (LDLr) expression

Summary

Introduction

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. 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.—Tancevski, I., A. TH were demonstrated to upregulate scavenger receptor class B, type I (SR-BI) in mice, an important component of reverse cholesterol transport (RCT) [6]. By their dual action on LDLr and SR-BI, THs could be expected to potently counteract the process of atherosclerosis. TH receptors were shown to occur in different isoforms where the a-variant regulates heart rate, and the b-isoform, abundant in the liver, mediates the effect of TH on lipids [7, 8]

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Results

Conclusion