Modos de ligação e interação entre mediadores lipídicos das séries Ômega-3 e Ômega-6 e o receptor ativado por proliferadores de peroxissomo gama (PPARy)

Abstract

Peroxisome Proliferator-Activated Receptors (PPARs) are transcription factors that belong to the Nuclear Receptor (NR) superfamily and play fundamental roles in the regulation of genes involved in lipid and carbohydrate metabolism, regulation of the inflammatory response, and control of cell differentiation. Three isotypes are expressed in the human body: PPARα, PPARβ/δ and PPARγ, each with distinct tissue distribution and functions. Structurally, PPARs have domains in common with most NRs, and their transcriptional activity depends on heterodimerization with another NR, the Retinoid X Receptor RXR, and on activation by agonist molecules, which trigger conformational changes essential for the recruitment of coactivator proteins and the initiation of transcription of target genes. The great interest in the effects of PPARγ in improving insulin sensitivity has led to the discovery of its role as immunomodulator agent and of its genuine natural ligands, fatty acids and their oxidized metabolites, such as oxylipins, generated by stimuli from the inflammatory microenvironment. These ligands include the n-3 and n-6 series essential fatty acids (EFAs) and their derivatives, which act as lipid mediators (LMs), significantly influencing the resolution of inflammatory processes. Although full PPARγ agonists, such as thiazolidinediones (TZDs), are effective in improving insulin sensitivity, their considerable adverse effects boosted the search for partial agonists, usually natural ligands, such as LMs, as alternatives for PPARγ activation with reduced adverse effects. Through a systematic search on PDB, 20 PPARγ complexes were identified with 17 different n-3 and n-6 LMs bound to the receptor’s ligand binding site. Based on these crystals and on experimental and computational studies, this review details the binding modes and interactions between PPARγ ligand binding site’s amino acid residues and its potential agonist MLs, also highlighting the conformational changes of crucial regions for receptor activation, such as the Ω-loop, beta sheets and -helices H3 and H12, resulting from the interactions with different ligands. The findings made evident the complexity and diversity of the interactions of MLs n-3 and n-6 with PPARγ, highlighting key residues for the rational design of new drugs that mimic endogenous ligands and selectively modulate receptor activity. In addition to reaffirming the importance of a diet, that provides optimal amounts of EFAs for immune and metabolic homeostasis, a deeper understanding of the mechanisms of binding and activation of PPARγ by its natural endogenous ligands has proven crucial for the development of new agonists that achieve effective and safer therapeutic results.