The Liver-Selective Thyromimetic T-0681 Influences Reverse Cholesterol Transport and Atherosclerosis Development in Mice

Ivan Tancevski*, 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

*Corresponding author for this work

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    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.

    Original languageEnglish
    Article number8722
    Number of pages8
    JournalPLoS ONE
    Volume5
    Issue number1
    DOIs
    Publication statusPublished - 15-Jan-2010

    Keywords

    • ESTER TRANSFER PROTEIN
    • RECEPTOR CLASS-B
    • DENSITY-LIPOPROTEIN RECEPTOR
    • IN-VIVO
    • LESION DEVELOPMENT
    • LDL CHOLESTEROL
    • SR-BI
    • OVEREXPRESSION
    • ABSORPTION
    • EXPRESSION

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