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

Tancevski I, Demetz E, Eller P, Duwensee K, Hoefer J, Heim C, Stanzl U, Wehinger A, Auer K, Karer R, Huber J, Schgoer W, Van Eck M, Vanhoutte J, Fievet C, Stellaard F, Rudling M, Patsch JR, Ritsch A - PLoS ONE (2010)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria. ivan.tancevski@i-med.ac.at

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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Influence of T-0681 on macrophage reverse cholesterol transport in vivo.(A) WT mice were treated with T-0681 (36 nmol/kg/d) or PBS, and the treatment was continued during the 48-hours RCT study. 12 days into treatment, cholesterol-loaded, [3H]-labeled J774 macrophages were injected intraperitoneally, and 48 hours later tracer was measured in plasma, liver, and fecal sterols (N = 10). (B) Macrophage in vivo RCT in CETP Tg mice was performed as described in (A) (N = 5); inset: Western blot showing hepatic expression of LDLr and SR-BI; each lane represents pooled protein extracts from 5 mice per group. **P<0.01, ***P<0.001 versus corresponding control.
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pone-0008722-g002: Influence of T-0681 on macrophage reverse cholesterol transport in vivo.(A) WT mice were treated with T-0681 (36 nmol/kg/d) or PBS, and the treatment was continued during the 48-hours RCT study. 12 days into treatment, cholesterol-loaded, [3H]-labeled J774 macrophages were injected intraperitoneally, and 48 hours later tracer was measured in plasma, liver, and fecal sterols (N = 10). (B) Macrophage in vivo RCT in CETP Tg mice was performed as described in (A) (N = 5); inset: Western blot showing hepatic expression of LDLr and SR-BI; each lane represents pooled protein extracts from 5 mice per group. **P<0.01, ***P<0.001 versus corresponding control.

Mentions: Recently, Rader and coworkers developed the first in vivo method to trace RCT specifically from macrophages to feces [15]. After intraperitoneal injection of [3H]-cholesterol-labeled macrophages, the tracer is measured in plasma, liver, and feces. In our experiments, T-0681 treated WT mice showed a strong decrease of plasma [3H]-cholesterol levels and no changes in hepatic tracer content. Most importantly, fecal excretion of neutral and acidic sterols was significantly increased in T-0681-treated animals (Figure 2A). Similar effects were observed in macrophage RCT studies using primary murine bone marrow-derived macrophages (data not shown). Our data resemble the results from macrophage RCT studies in SR-BI overexpressing animals [16]. In addition to increased hepatic SR-BI expression, our mice also exhibited increased hepatobiliary secretion of sterols via ABCG5/G8 and CYP7A1, which may substantially contribute to the promotion of RCT by T-0681.


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

Tancevski I, Demetz E, Eller P, Duwensee K, Hoefer J, Heim C, Stanzl U, Wehinger A, Auer K, Karer R, Huber J, Schgoer W, Van Eck M, Vanhoutte J, Fievet C, Stellaard F, Rudling M, Patsch JR, Ritsch A - PLoS ONE (2010)

Influence of T-0681 on macrophage reverse cholesterol transport in vivo.(A) WT mice were treated with T-0681 (36 nmol/kg/d) or PBS, and the treatment was continued during the 48-hours RCT study. 12 days into treatment, cholesterol-loaded, [3H]-labeled J774 macrophages were injected intraperitoneally, and 48 hours later tracer was measured in plasma, liver, and fecal sterols (N = 10). (B) Macrophage in vivo RCT in CETP Tg mice was performed as described in (A) (N = 5); inset: Western blot showing hepatic expression of LDLr and SR-BI; each lane represents pooled protein extracts from 5 mice per group. **P<0.01, ***P<0.001 versus corresponding control.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2806908&req=5

pone-0008722-g002: Influence of T-0681 on macrophage reverse cholesterol transport in vivo.(A) WT mice were treated with T-0681 (36 nmol/kg/d) or PBS, and the treatment was continued during the 48-hours RCT study. 12 days into treatment, cholesterol-loaded, [3H]-labeled J774 macrophages were injected intraperitoneally, and 48 hours later tracer was measured in plasma, liver, and fecal sterols (N = 10). (B) Macrophage in vivo RCT in CETP Tg mice was performed as described in (A) (N = 5); inset: Western blot showing hepatic expression of LDLr and SR-BI; each lane represents pooled protein extracts from 5 mice per group. **P<0.01, ***P<0.001 versus corresponding control.
Mentions: Recently, Rader and coworkers developed the first in vivo method to trace RCT specifically from macrophages to feces [15]. After intraperitoneal injection of [3H]-cholesterol-labeled macrophages, the tracer is measured in plasma, liver, and feces. In our experiments, T-0681 treated WT mice showed a strong decrease of plasma [3H]-cholesterol levels and no changes in hepatic tracer content. Most importantly, fecal excretion of neutral and acidic sterols was significantly increased in T-0681-treated animals (Figure 2A). Similar effects were observed in macrophage RCT studies using primary murine bone marrow-derived macrophages (data not shown). Our data resemble the results from macrophage RCT studies in SR-BI overexpressing animals [16]. In addition to increased hepatic SR-BI expression, our mice also exhibited increased hepatobiliary secretion of sterols via ABCG5/G8 and CYP7A1, which may substantially contribute to the promotion of RCT by T-0681.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria. ivan.tancevski@i-med.ac.at

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.

Show MeSH
Related in: MedlinePlus