title: The thyroid receptor modulator KB3495 reduces atherosclerosis independently of total cholesterol in the circulation in ApoE deficient mice.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
authors: Lisa-Mari
authors: LM
authors: Mörk
authors: Stefan
authors: S
authors: Rehnmark
authors: Padideh
authors: P
authors: Davoodpour
authors: Giuseppe Danilo
authors: GD
authors: Norata
authors: Lilian
authors: L
authors: Larsson
authors: Michael-Robin
authors: MR
authors: Witt
authors: Johan
authors: J
authors: Malm
authors: Paolo
authors: P
authors: Parini
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001055:Apolipoproteins B / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000069059:Atorvastatin; D001647:Bile Acids and Salts / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D004195:Disease Models, Animal; D004357:Drug Synergism; D005243:Feces / Q000737:chemistry; D006538:Heptanoic Acids / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018716:Molecular Mimicry; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011758:Pyrroles / Q000494:pharmacology*; D013963:Thyroid Hormones / Q000737:chemistry
chemical_list: D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; D001057:Apolipoproteins E; D001647:Bile Acids and Salts; D016207:Cytokines; D006538:Heptanoic Acids; D011758:Pyrroles; D013963:Thyroid Hormones; D000069059:Atorvastatin