Synthetic LXR agonist inhibits the development of atherosclerosis in New Zealand White rabbits

Biochim Biophys Acta. 2011 Dec;1811(12):1136-45. doi: 10.1016/j.bbalip.2011.08.009. Epub 2011 Aug 19.

Abstract

The nuclear receptors Liver X receptors, LXRα and LXRβ, regulate cholesterol and triglyceride metabolism. We and others have previously reported that synthetic LXR agonists reduced atherosclerosis in models of mouse with no detectable plasma cholesteryl ester transfer protein (CETP) activity, which plays an important role in reverse cholesterol transport. In the present study, we investigated the effect of LXR activation in rabbits to elucidate the influence of CETP activity. First, we cloned rabbit LXRs cDNA. The data indicated that rabbit LXRα was mostly highly expressed in the liver, whereas LXRβ expression was ubiquitous. Next, we investigated the effect of LXR agonist on lipid levels. Treatment with LXR agonist T0901317 increased plasma CETP activity and consequently elevated LDL, but no change in HDL. High cholesterol (HC) diet-feeding, which is thought to provide oxysterols as the natural agonists, could also increase expression of CETP and other LXR target genes. Finally, we tested T0901317 in the atherosclerosis intervention study. Chronic administration of T0901317 significantly reduced atherosclerosis in HC diet-fed rabbits despite less favorable lipid profiles, i.e. increases of plasma triglycerides and no change of HDL. T0901317 induced ATP-binding cassette transporters ABCA1 and ABCG1 and suppressed inflammatory genes expression in the aorta, suggesting that direct actions of LXR agonist on vascular gene expression are likely to contribute to the antiatherogenic effect. The present work strongly supports the idea that LXR agonists could be beneficial as therapeutic agents for treatment of atherosclerosis.

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Amino Acid Sequence
  • Animals
  • Anticholesteremic Agents / pharmacology
  • Aorta / drug effects
  • Aorta / metabolism
  • Atherosclerosis / blood*
  • Atherosclerosis / drug therapy
  • Atherosclerosis / etiology
  • Atherosclerosis / genetics
  • Cholesterol / blood
  • Cholesterol / pharmacology
  • Cholesterol Ester Transfer Proteins / blood*
  • Cholesterol Ester Transfer Proteins / genetics
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Gene Expression* / drug effects
  • Hydrocarbons, Fluorinated / pharmacology*
  • Lipoproteins, HDL / blood
  • Lipoproteins, LDL / blood
  • Liver / drug effects
  • Liver / metabolism
  • Liver X Receptors
  • Molecular Sequence Data
  • Orphan Nuclear Receptors / agonists*
  • Orphan Nuclear Receptors / metabolism
  • Rabbits
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction* / drug effects
  • Sulfonamides / pharmacology*
  • Triglycerides / blood

Substances

  • ATP-Binding Cassette Transporters
  • Anticholesteremic Agents
  • Cholesterol Ester Transfer Proteins
  • Hydrocarbons, Fluorinated
  • Lipoproteins, HDL
  • Lipoproteins, LDL
  • Liver X Receptors
  • Nr1h3 protein, mouse
  • Orphan Nuclear Receptors
  • Recombinant Proteins
  • Sulfonamides
  • TO-901317
  • Triglycerides
  • Cholesterol