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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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Relative contribution of SR-BI and LDLr to the cholesterol-lowering action of T-0681.(A) FPLC analysis of pooled plasma from SR-BI KO mice with and without T-0681 treatment (36 nmol/kg/d; N = 4); inset: Western blot showing hepatic expression of LDLr; each lane represents pooled protein extracts from 4 mice per group. (B) FPLC analysis of pooled plasma from LDLr KO mice with and without T-0681 treatment (36 nmol/kg/d; N = 4); inset: Western blot showing hepatic expression of SR-BI; each lane represents pooled protein extracts from 4 mice per group.
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pone-0008722-g003: Relative contribution of SR-BI and LDLr to the cholesterol-lowering action of T-0681.(A) FPLC analysis of pooled plasma from SR-BI KO mice with and without T-0681 treatment (36 nmol/kg/d; N = 4); inset: Western blot showing hepatic expression of LDLr; each lane represents pooled protein extracts from 4 mice per group. (B) FPLC analysis of pooled plasma from LDLr KO mice with and without T-0681 treatment (36 nmol/kg/d; N = 4); inset: Western blot showing hepatic expression of SR-BI; each lane represents pooled protein extracts from 4 mice per group.

Mentions: Interestingly, we found a marked increase in LDLr expression in the liver of CETP-expressing animals treated with T-0681, including the here presented CETP Tg mice (Figure 2B, inset), as well as in the recently studied hypercholesterolemic New Zealand White (NZW) rabbits [10], which naturally express plasma CETP. Moreover, T-0681 significantly increased hepatic LDLrs in SR-BI KO mice (2-fold of controls, P<0.01), along with a marked decrease in plasma cholesterol (Figure 3A). In contrast, T-0681 did not affect plasma cholesterol in LDLr KO mice nor did it induce the hepatic expression of SR-BI (Figure 3B). Regulation of hepatic CYP7A1 and ABCG5/G8 is summarized in Table 1.


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)

Relative contribution of SR-BI and LDLr to the cholesterol-lowering action of T-0681.(A) FPLC analysis of pooled plasma from SR-BI KO mice with and without T-0681 treatment (36 nmol/kg/d; N = 4); inset: Western blot showing hepatic expression of LDLr; each lane represents pooled protein extracts from 4 mice per group. (B) FPLC analysis of pooled plasma from LDLr KO mice with and without T-0681 treatment (36 nmol/kg/d; N = 4); inset: Western blot showing hepatic expression of SR-BI; each lane represents pooled protein extracts from 4 mice per group.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0008722-g003: Relative contribution of SR-BI and LDLr to the cholesterol-lowering action of T-0681.(A) FPLC analysis of pooled plasma from SR-BI KO mice with and without T-0681 treatment (36 nmol/kg/d; N = 4); inset: Western blot showing hepatic expression of LDLr; each lane represents pooled protein extracts from 4 mice per group. (B) FPLC analysis of pooled plasma from LDLr KO mice with and without T-0681 treatment (36 nmol/kg/d; N = 4); inset: Western blot showing hepatic expression of SR-BI; each lane represents pooled protein extracts from 4 mice per group.
Mentions: Interestingly, we found a marked increase in LDLr expression in the liver of CETP-expressing animals treated with T-0681, including the here presented CETP Tg mice (Figure 2B, inset), as well as in the recently studied hypercholesterolemic New Zealand White (NZW) rabbits [10], which naturally express plasma CETP. Moreover, T-0681 significantly increased hepatic LDLrs in SR-BI KO mice (2-fold of controls, P<0.01), along with a marked decrease in plasma cholesterol (Figure 3A). In contrast, T-0681 did not affect plasma cholesterol in LDLr KO mice nor did it induce the hepatic expression of SR-BI (Figure 3B). Regulation of hepatic CYP7A1 and ABCG5/G8 is summarized in Table 1.

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