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

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.

Lipid lowering with thyroid hormone and thyromimetics

“…In agreement with this reasoning, evidence of reduced atherosclerosis in animal models such as cholesterolfed rabbits [20 ] and apoE-knockout mice [19 ] has now been reported using the liver-selective thyromimetic T-0681.…”

Nuclear Receptors and Their Selective Pharmacologic Modulators

“…T-0681 induced the LDL and HDL receptors in rodents and in addition was found to significantly increase fecal excretion of macrophage-derived neutral and acidic sterols (Tancevski et al, 2010). Notably, no apparent positive effects on the process of reverse cholesterol transport could be found in CETP transgenic mice in the same study.…”

Rutaecarpine suppresses atherosclerosis in ApoE−/− mice through upregulating ABCA1 and SR-BI within RCT

“…Liver lipids, fecal cholesterol, and bile acid were extracted as described by Zhang et al (30)(31)(32)(33)(34). Briefl y, a 100 mg piece of liver tissue was homogenized in water and extracted three times with 9 ml chloroform-methanol (2:1, v/v).…”