Characterization of the interaction of nuclear receptor PPAR³ with the deacetylase SIRT1 under influence of its phosphorylation in the context of metabolic homeostasis regulation

Abstract

The Metabolic Syndrome is a cluster of conditions that happens together. These conditions disrupt the body glycose levels homeostasis, which leads to a resistance to respond to insulin. The thiazolidinediones (TZDs) are the main drug for the treatment of Metabolic Syndrome. It targets the ligate-dependent nuclear receptor (RN) PPAR³ where it acts as a strong agonist. The PPAR³ is a key player in improving insulin sensitivity once activated. It acts as a transcriptional factor changing the level of expression in a subset of genes related to insulin resistance. However, the long-term administration of TZDs in comorbid patients has been in intense discussion. Besides its beneficial effects of PPAR³ activation, the TZDs also cause adverse effects to the patients, worsening this clinical condition. Its already know that the balance between PPAR³ posttranscriptional modifications (MPT) as phosphorylation at Lis293 and Lis268 for CDK5 and the acetylation/deacetylation at Lis293 and Lis268 p300/SIRT1 drive to benefits effects to the organism. Based on this, this project aims (1) to characterize in vitro the molecular basis of PPAR³:SIRT complex and (2) investigate the influence of phosphorylation from CDK5 in that relationship. In addition, we will search for new potential molecular that could act as a partial agonist of PPAR³, activating it without causing any damage to the patient. In this investigation, we intend to determine the affinity between PPAR³:SIRT1 by biophysical techniques and the structure of the complex as well. Furthermore, a screening for new molecules able to act as a partial agonist also we shall perform. In parallel, colleagues also will execute in vivo characterization for a robust and multi multidisciplinary approach towards a better understanding of proposed goals. (AU)