The liver-selective thyromimetic T-0681 influences reverse cholesterol transport and atherosclerosis development in mice

  • PLoS One. 2010 Jan 15;5(1):e8722. doi: 10.1371/journal.pone.0008722.
Ivan Tancevski  1 ,  Egon Demetz ,  Philipp Eller ,  Kristina Duwensee ,  Julia Hoefer ,  Christiane Heim ,  Ursula Stanzl ,  Andreas Wehinger ,  Kristina Auer ,  Regina Karer ,  Julia Huber ,  Wilfried Schgoer ,  Miranda Van Eck ,  Jonathan Vanhoutte ,  Catherine Fievet ,  Frans Stellaard ,  Mats Rudling ,  Josef R Patsch ,  Andreas Ritsch
Affiliations
  • 1. Department of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria. [email protected]
PMID: 20090943 DOI: 10.1371/journal.pone.0008722
Abstract

Background: Liver-selective thyromimetics have been reported to efficiently reduce plasma Cholesterol through the hepatic induction of both, the low-density lipoprotein receptor (LDLR) and the high-density lipoprotein (HDL) receptor; the scavenger receptor class B type I (SR-BI). Here, we investigated the effect of the thyromimetic T-0681 on reverse Cholesterol transport (RCT) and atherosclerosis, and studied the underlying mechanisms using different mouse models, including mice lacking LDLR, SR-BI, and apoE, as well as CETP transgenic mice.

Methodology/principal findings: T-0681 treatment promoted bile acid production and biliary sterol secretion consistently in the majority of the studied mouse models, which was associated with a marked reduction of plasma Cholesterol. Using an assay of macrophage RCT in mice, we found T-0681 to significantly increase fecal excretion of macrophage-derived neutral and acidic sterols. No positive effect on RCT was found in CETP transgenic mice, most likely due to the observed decrease in plasma CETP mass. Studies in SR-BI KO and LDLR KO mice suggested hepatic LDLR to be necessary for the action of T-0681 on lipid metabolism, as the compound did not have any influence on plasma Cholesterol levels in mice lacking this receptor. Finally, prolonged treatment with T-0681 reduced the development of atherosclerosis by 60% in apoE KOs on Western type diet. In contrast, at an earlier time-point T-0681 slightly increased small fatty streak lesions, in part due to an impaired macrophage Cholesterol efflux capacity, when compared to controls.

Conclusions/significance: The present results show that liver-selective thyromimetics can promote RCT and that such compounds may protect from atherosclerosis partly through induction of bile acid metabolism and biliary sterol secretion. On-going clinical trials will show whether selective thyromimetics do prevent atherosclerosis also in humans.

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