[Show abstract][Hide abstract] 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.
No preview · Article · Aug 2011 · Biochimica et Biophysica Acta
[Show abstract][Hide abstract] ABSTRACT: Liver X receptors (LXRs), LXRalpha and LXRbeta, are members of the nuclear receptor superfamily and regulate the expression of genes involved in the regulation of cholesterol and fatty acid metabolism. Human plasma, unlike mouse plasma, contains cholesteryl ester transfer protein (CETP), which plays an important role in reverse cholesterol transport (RCT). LXRs induce CETP transcription via a direct repeat 4 element in the CETP promoter. However, the specific roles of the individual LXR subtypes in CETP expression and their consequences on plasma lipoprotein metabolism are still unclear. Here we showed that synthetic LXR agonist enhanced plasma CETP activity and resulted in non-high density lipoprotein (non-HDL) increase and HDL decrease in cynomolgus monkeys and human CETP transgenic mice. To address the relative importance of the two LXR subtypes, we investigated the effect of the suppression of both LXR subtypes on CETP expression in HepG2 cells. CETP expression induced by the LXR agonist was significantly reduced by LXRalpha knock-down, but not by LXRbeta. Consistent with these data, CETP promoter activity was enhanced by LXRalpha activation, whereas LXRbeta activation had only a minor effect. Furthermore, we investigated the effect of genetic deficiency of both LXR subtypes in human CETP transgenic mice. LXRalpha deficiency abolished the augmentation of plasma CETP activity and hepatic CETP expression induced by the synthetic LXR agonist, consequently increasing HDL and decreasing non-HDL, whereas LXRbeta deficiency did not affect CETP activation. These findings indicate that LXRalpha has an essential role in the regulation of CETP expression and maintaining RCT.