Abstract
BackgroundLiver-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 FindingsT-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/SignificanceThe 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.
Highlights
It has been known since 1930 that hyperthyroidism is associated with reduced plasma cholesterol levels [1, reviewed in 2], and since many efforts were made to exploit the ability of thyroid hormones (TH) to lower cholesterol
Conclusions/Significance: The present results show that liver-selective thyromimetics can promote reverse cholesterol transport (RCT) and that such compounds may protect from atherosclerosis partly through induction of bile acid metabolism and biliary sterol secretion
We previously showed that prolonged treatment with the liverselective thyromimetic T-0681 dramatically reduced the atherosclerotic lesion area in New Zealand White (NZW) rabbits [10]
Summary
It has been known since 1930 that hyperthyroidism is associated with reduced plasma cholesterol levels [1, reviewed in 2], and since many efforts were made to exploit the ability of thyroid hormones (TH) to lower cholesterol. With the introduction into clinical practice of HMG-CoA reductase inhibitors, usually known as ‘statins’, to lower plasma cholesterol in the mid 1980s, efforts on the development of TH analogs slowed. The last 20 years saw the development of thyromimetic compounds selective for the liver and/or the b1-isoform of the TH receptor which all were shown to efficiently lower plasma cholesterol without concomitant deleterious effects on the heart [4,5]. Several selective thyromimetics have been shown to be useful lipid-lowering compounds in animal studies [6,7,8] resulting in clinical trials [9]. 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). 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
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