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


RESULTS
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
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.
Tancevski
Ivan
I
Department of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria. ivan.tancevski@i-med.ac.at
Demetz
Egon
E
Eller
Philipp
P
Duwensee
Kristina
K
Hoefer
Julia
J
Heim
Christiane
C
Stanzl
Ursula
U
Wehinger
Andreas
A
Auer
Kristina
K
Karer
Regina
R
Huber
Julia
J
Schgoer
Wilfried
W
Van Eck
Miranda
M
Vanhoutte
Jonathan
J
Fievet
Catherine
C
Stellaard
Frans
F
Rudling
Mats
M
Patsch
Josef R
JR
Ritsch
Andreas
A
D000818:Animals; D050197:Atherosclerosis / Q000517:prevention & control*; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D004195:Disease Models, Animal; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008314:Malonates / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D010647:Phenyl Ethers / Q000494:pharmacology*
D008314:Malonates; C496199:N-(4-(3-((4-fluorophenyl)hydroxymethyl)-4-hydroxyphenoxy)-3,5-dimethylphenyl) malonamic acid sodium; D010647:Phenyl Ethers; D002784:Cholesterol