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The Thyroid Receptor Modulator KB3495 Reduces Atherosclerosis Independently of Total Cholesterol in the Circulation in ApoE Deficient Mice
BACKGROUND: Thyroid 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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3850901/ https://www.ncbi.nlm.nih.gov/pubmed/24324578 http://dx.doi.org/10.1371/journal.pone.0078534 |
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author | Mörk, Lisa-Mari Rehnmark, Stefan Davoodpour, Padideh Norata, Giuseppe Danilo Larsson, Lilian Witt, Michael-Robin Malm, Johan Parini, Paolo |
author_facet | Mörk, Lisa-Mari Rehnmark, Stefan Davoodpour, Padideh Norata, Giuseppe Danilo Larsson, Lilian Witt, Michael-Robin Malm, Johan Parini, Paolo |
author_sort | Mörk, Lisa-Mari |
collection | PubMed |
description | BACKGROUND: Thyroid 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. OBJECTIVE: Using 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. RESULTS: KB3495 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. CONCLUSION: KB3495 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. |
format | Online Article Text |
id | pubmed-3850901 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-38509012013-12-09 The Thyroid Receptor Modulator KB3495 Reduces Atherosclerosis Independently of Total Cholesterol in the Circulation in ApoE Deficient Mice Mörk, Lisa-Mari Rehnmark, Stefan Davoodpour, Padideh Norata, Giuseppe Danilo Larsson, Lilian Witt, Michael-Robin Malm, Johan Parini, Paolo PLoS One Research Article BACKGROUND: Thyroid 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. OBJECTIVE: Using 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. RESULTS: KB3495 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. CONCLUSION: KB3495 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. Public Library of Science 2013-12-04 /pmc/articles/PMC3850901/ /pubmed/24324578 http://dx.doi.org/10.1371/journal.pone.0078534 Text en © 2013 Mörk et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Mörk, Lisa-Mari Rehnmark, Stefan Davoodpour, Padideh Norata, Giuseppe Danilo Larsson, Lilian Witt, Michael-Robin Malm, Johan Parini, Paolo The Thyroid Receptor Modulator KB3495 Reduces Atherosclerosis Independently of Total Cholesterol in the Circulation in ApoE Deficient Mice |
title | The Thyroid Receptor Modulator KB3495 Reduces Atherosclerosis Independently of Total Cholesterol in the Circulation in ApoE Deficient Mice |
title_full | The Thyroid Receptor Modulator KB3495 Reduces Atherosclerosis Independently of Total Cholesterol in the Circulation in ApoE Deficient Mice |
title_fullStr | The Thyroid Receptor Modulator KB3495 Reduces Atherosclerosis Independently of Total Cholesterol in the Circulation in ApoE Deficient Mice |
title_full_unstemmed | The Thyroid Receptor Modulator KB3495 Reduces Atherosclerosis Independently of Total Cholesterol in the Circulation in ApoE Deficient Mice |
title_short | The Thyroid Receptor Modulator KB3495 Reduces Atherosclerosis Independently of Total Cholesterol in the Circulation in ApoE Deficient Mice |
title_sort | thyroid receptor modulator kb3495 reduces atherosclerosis independently of total cholesterol in the circulation in apoe deficient mice |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3850901/ https://www.ncbi.nlm.nih.gov/pubmed/24324578 http://dx.doi.org/10.1371/journal.pone.0078534 |
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