A Synthetic Liver X Receptor Agonist T0901317 Inhibits Atherosclerosis And Increases ABCA1 Gene And Protein Expression In ApoE-/- Mice

OBJECTIVE Liver X receptors (LXRs), which are members of nuclear receptor super-family, have been found to induce a number of genes involved in the regulation of cellular cholesterol efflux, intestinal cholesterol absorption, and hepatic lipid synthesis. However, the ability of LXR-signaling pathways to have an impact on multiple aspects of systemic lipid metabolism makes the long-term effects of synthetic LXR agonists difficult to predict. So, in the present study we want to examine the effect of LXR on atherosclerotic lesions and ATP-binding cassette transporter A1 (ABCA1) gene and protein expression by treating apoE-/- mice with a synthetic LXR agonist T0901317 and explore new potential mechanism of inhibiting atherosclerosis for LXR activation.MEHTODS Male apoE-/- mice were randomly divided into four groups, baseline group (n=10), vehicle group (n=14), prevention group (n=14) and treatment group (n=14). All of the mice were fed a high-fat/high-cholesterol diet (15% fat wt/wt, 0.25% cholesterol wt/wt) with or without LXR agonist T0901317 (10 mg/kg/d) for 8 or 14 weeks. En face analysis and oil red O staining was used to examine the aortic atherosclerotic lesions. Plasma triglyceride (TG), total cholesterol (TC), and high density lipoprotein cholesterol (HDL-C) were determined by commercially enzymatic methods. Apolipoprotein A-I (apoA-I) and apoB were measured by immunoturbidimetry. Lipid deposition in the liver is detected by Oil red O staining. Gene and protein expression was analyzed by semi-quantitative RT-PCR, gene microarray, real-time quantitative PCR, immunohistochemistry and Western blot, respectively.RESULTS T0901317 treatment resulted in a significant reduction of atherosclerotic lesion area in prevention group and treatment group compared with vehicle-treated controls. Plasma TG, TC, HDL-C and apoA-I concentrations were markedly increased in prevention group and treatment group. T0901317 contributed to a significant increase of lipid content in the liver of apoE-/- mice. T0901317 positively regulated hepatic gene expression of LXRα, ABCA1, ABCG1 and sterol regulatory element-binding protein-1c (SREBP-1c) in apoE-/- mice. Furthermore, gene array analysis showed that LXR activation resulted in increased mRNA expression of LXR target genes, LXRαand ABCA1, and decreased mRNA expression of some proinflammatory genes including interleukin-1α(IL-1α), IL-6, and IL-7 in the liver. T0901317 also promoted ABCA1 gene and protein expression in the aorta, liver, small intestine and brain.CONCLUSION The synthetic LXR agonist T0901317 has a strong preventive and therapeutic effect on the atherosclerotic lesions in apoE-/- mice. The mechanism of this action for T0901317 is associated with the downregulation of proinflammatory gene, such as IL-1α, IL-6, and IL-7. T0901317 elevates ABCA1 gene and protein expression in the aorta, liver, small intestine and brain.