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

• Grant number: 17/12314-0
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Effective date (Start): September 14, 2017
• Effective date (End): January 16, 2018
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Ana Carolina Migliorini Figueira
• Grantee: Thaís Helena Tittanegro
• Supervisor: Matthew Charles Gage
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovações (Brasil). Campinas , SP, Brazil
• Research place: University College London (UCL), England
• Associated to the scholarship: 16/13480-9 - Identification of the mechanisms of phosphorylation of PPARy and its relations with the recruitment of corepressors, BP.MS

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)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

GAGE, M. C.; BECARES, N.; LOUIE, R.; WADDINGTON, K. E.; ZHANG, Y.; TITTANEGRO, T. H.; RODRIGUEZ-LORENZO, S.; JATHANNA, A.; POURCET, B.; PELLO, O. M.; et al. Disrupting LXRa phosphorylation promotes FoxM1 expression and modulates atherosclerosis by inducing macrophage proliferation. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v. 115, n. 28, p. E6556-E6565, JUL 10 2018. (17/12314-0)