Abstract
BackgroundThyroid hormones (TH) regulate cholesterol metabolism but their use as lipid-lowering drugs is restricted due to negative cardiac effects. TH mimetic compounds modulating TH receptor β (THRβ) have been designed as potential drugs, reducing serum cholesterol levels while avoiding apparent deleterious cardiac effects. ObjectiveUsing ApoE deficient mice, we examined whether KB3495, a TH mimetic compound, reduces atherosclerosis and if there is a synergistic effect with atorvastatin. The effect of KB3495 was investigated after 10 and 25 weeks.ResultsKB3495 treatment reduced atherosclerotic plaque formation in aorta and decreased the cholesteryl ester (CE) content by 57%. Treatment with KB3495 was also associated with a reduction of macrophage content in the atherosclerotic plaques and reduced serum levels of IL-1β, TNFalpha, IL-6, Interferon γ, MCP-1 and M-CSF. Serum lipoprotein analysis showed no change in total cholesterol levels in ApoB-containing lipoproteins. KB3495 alone increased fecal BA excretion by 90%. The excretion of neutral sterols increased in all groups, with the largest increase in the combination group (350%). After 25 weeks, the animals treated with KB3495 showed 50% lower CE levels in the skin and even further reductions were observed in the combination group where the CE levels were reduced by almost 95% as compared to controls. ConclusionKB3495 treatment reduced atherosclerosis independently of total cholesterol levels in ApoB-containing lipoproteins likely by stimulation of sterol excretion from the body and by inhibition of the inflammatory response.
Highlights
The first-choice treatment to decrease low density lipoprotein cholesterol (LDL-C) and reduce the risk for atherosclerosis are 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors [1]
Treatment with KB3495 was associated with a reduction of macrophage content in the atherosclerotic plaques and reduced serum levels of IL-1β, TNFalpha, IL-6, Interferon γ, monocyte chemotactic protein-1 (MCP-1) and Macrophage colony-stimulating factor (M-CSF)
The excretion of neutral sterols increased in all groups, with the largest increase in the combination group (350%)
Summary
The first-choice treatment to decrease low density lipoprotein cholesterol (LDL-C) and reduce the risk for atherosclerosis are 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors (statins) [1]. Newer drugs like ezetimibe, which acts by blocking intestinal cholesterol uptake, have recently been proposed as complements to statin therapy Despite these new therapeutic approaches there still is a demand for improved treatment strategies. TH mimetic compounds that modulate TRβ either by selective hepatic uptake and/or by higher binding affinity to TRβ, have been designed as potential drugs, one compound has been tested in the clinic [9,10]. These substances have been shown to reduce serum cholesterol while avoiding apparent side-effects on the heart [11,12,13]. TH mimetic compounds modulating TH receptor β (THRβ) have been designed as potential drugs, reducing serum cholesterol levels while avoiding apparent deleterious cardiac effects
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