Inhibition of LXR alpha phosphorylation: evaluating target gene expression effects and LXR alpha and PPAR gamma crosstalk

Abstract

PPARs and LXRs are lipid-activated transcription factors that belong to the nuclear receptor superfamily. Both types of receptors are activated by ligands from dietary lipids, such as fatty acids and cholesterol metabolites (oxysterols), respectively. They are intrinsically involved in metabolic pathways related to inflammation, diabetes, obesity and cardiovascular diseases, which make them potential targets for new therapeutic development. Several studies have reported the interaction between these two nuclear receptors regarding their crosstalk involved in macrophage activation, adiponectin production and vessel wall cell maintenance. Additionally, studies of animals submitted to caloric restriction have demonstrated changes in the expression profile of genes regulated by these two receptors. Moreover, it has also been shown that diets with high levels of fat and cholesterol in a novel mouse model, which have inhibited phosphorylation of LXR alpha at serine 196 residue, resulted in reduction in hepatic inflammation and fibrosis. Here we propose to study the relationship between PPAR gamma and LXR alpha expression profiles in two novel mouse models of LXR alpha phosphorylation deficiency, which are currently being used to investigate the effects of LXR alpha signalling on atherosclerosis, liver steatosis and fibrosis in which PPAR gamma is intimately linked. (AU)