The thyroid receptor modulator KB3495 reduces atherosclerosis independently of total cholesterol in the circulation in ApoE deficient mice

PloS One
Lisa-Mari MörkPaolo Parini

Abstract

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. 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. 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 ...Continue Reading

References

Jan 1, 1978·Scandinavian Journal of Clinical and Laboratory Investigation. Supplementum·M P Gillett
Sep 1, 1977·Clinica Chimica Acta; International Journal of Clinical Chemistry·J de WaelH J Endeman
Apr 1, 1989·Scandinavian Journal of Clinical and Laboratory Investigation·E LundI Bjorkhem
Jul 31, 1974·Clinica Chimica Acta; International Journal of Clinical Chemistry·I BjörkhemL Svensson
Sep 15, 1982·Clinica Chimica Acta; International Journal of Clinical Chemistry·T A Miettinen
Oct 1, 1980·Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Métabolisme·J FeelyM Bakry
Feb 1, 1995·The Journal of Investigative Dermatology·K R FeingoldN Maeda
Jul 8, 1998·Chemistry & Biology·G ChielliniT S Scanlan
Apr 27, 2000·Proceedings of the Society for Experimental Biology and Medicine·G C Ness, C M Chambers
Feb 15, 2001·The New England Journal of Medicine·I Klein, K Ojamaa
May 23, 2001·JAMA : the Journal of the American Medical Association·UNKNOWN Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
May 30, 2002·Thyroid : Official Journal of the American Thyroid Association·Leonidas H Duntas
Aug 10, 2002·American Journal of Physiology. Endocrinology and Metabolism·Roy E WeissRoberto Lang
Jul 31, 2003·Proceedings of the National Academy of Sciences of the United States of America·Gary J GroverJohn D Baxter
Oct 1, 2003·Trends in Endocrinology and Metabolism : TEM·J H Duncan Bassett, Graham R Williams
Jul 5, 2005·Biochimica Et Biophysica Acta·Charlotte MurphyMats Gåfvels
Jul 12, 2005·Proceedings of the National Academy of Sciences of the United States of America·Lisen JohanssonPaolo Parini
Jan 27, 2006·European Journal of Clinical Investigation·P PariniM Rudling
Jun 19, 2007·Biochimica Et Biophysica Acta·Dayami LopezGene C Ness
Sep 20, 2007·Proceedings of the National Academy of Sciences of the United States of America·Mark D ErionDavid L Linemeyer
Dec 28, 2007·Proceedings of the National Academy of Sciences of the United States of America·Anders BerkenstamJohn D Baxter
May 31, 2008·American Journal of Physiology. Gastrointestinal and Liver Physiology·Astrid E van der VeldeAlbert K Groen
Apr 2, 2009·Nature Reviews. Drug Discovery·John D Baxter, Paul Webb
Mar 12, 2010·The New England Journal of Medicine·Paul W LadensonBo Angelin
Apr 29, 2010·Current Atherosclerosis Reports·Amit V Khera, Daniel J Rader

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Citations

Aug 17, 2014·Trends in Endocrinology and Metabolism : TEM·Rohit A SinhaPaul M Yen
Feb 18, 2016·Current Atherosclerosis Reports·L P B ElbersB Sjouke
Apr 1, 2017·International Journal of Molecular Sciences·Fabrizio DamianoLuisa Siculella
Jan 11, 2016·Acta Physiologica·D GnocchiP Parini

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Methods Mentioned

BETA
biopsies
PCR
column chromatography

Software Mentioned

MicroMorph
Stat Soft
Statistica
Leica Q500

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