The effect of T0901317 on ATP-binding cassette transporter A1 and Niemann-Pick type C1 in apoE-/- mice

J Cardiovasc Pharmacol. 2008 May;51(5):467-75. doi: 10.1097/FJC.0b013e31816a5be3.

Abstract

Although a range of studies indicated Liver X receptor (LXR) activation inhibited the development of atherosclerosis in animal models, the mechanism of this effect for LXR agonists has not been fully understood. A recent study has suggested LXR activators increased the amount of free cholesterol in the plasma membrane of human macrophages by inducing Niemann-Pick type C1 (NPC1) gene expression. Therefore, we hypothesize that LXRs may also promote NPC1 expression in vivo. Here we investigated the effect of a synthetic LXR agonist T0901317 on ATP-binding cassette transporter A1 (ABCA1) and NPC1 in apolipoprotein E knockout (apoE-/-) mice. Male apoE-/- mice were randomized into four groups: baseline group (n = 10), vehicle group (n = 14), prevention group (n = 14), and treatment group (n = 14). En face analysis and Oil red O staining were used to examine the aortic atherosclerotic lesions. Macrophage content of aortic root atherosclerotic lesions and cholesterol efflux form peritoneal macrophages were measured. Gene and protein expression was analyzed by real-time quantitative polymerase chain reaction and Western blotting, respectively. T0901317 treatment reduced aortic atherosclerotic lesion area by 64.2% in prevention group (P < 0.001) and 58.3% in treatment group (P < 0.001) and resulted in a reduction in macrophage content. Plasma triglyceride, total cholesterol, high-density lipoprotein cholesterol, and apoA-I concentrations were markedly increased in T0901317-treated groups. T0901317 also promoted ABCA1 and NPC1 gene and protein levels in the aorta, liver, and small intestine of apoE-/- mice and significantly increased cholesterol efflux from peritoneal macrophages. T0901317 upregulates ABCA1 and NPC1. This study gives us a new insight into the mechanism for antiatherogenic effect of LXR synthetic agonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters / metabolism*
  • Animals
  • Aorta / metabolism
  • Aorta / pathology
  • Apolipoproteins E / genetics*
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control
  • Blotting, Western
  • Cells, Cultured
  • Cholesterol / blood
  • Cholesterol / metabolism
  • DNA-Binding Proteins / agonists*
  • Hydrocarbons, Fluorinated
  • Intestine, Small / drug effects
  • Intestine, Small / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Liver / drug effects
  • Liver / metabolism
  • Liver X Receptors
  • Macrophages / metabolism
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Orphan Nuclear Receptors
  • Polymerase Chain Reaction
  • Proteins / metabolism*
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Sulfonamides / pharmacology*

Substances

  • ABCA1 protein, human
  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters
  • Apolipoproteins E
  • DNA-Binding Proteins
  • Hydrocarbons, Fluorinated
  • Intracellular Signaling Peptides and Proteins
  • Liver X Receptors
  • Npc1 protein, mouse
  • Orphan Nuclear Receptors
  • Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Sulfonamides
  • TO-901317
  • Cholesterol