The role of transcription coactivators PGC-1 in the inflammatory process

• Grant number: 12/07957-6
• Support Opportunities: Regular Research Grants
• Duration: August 01, 2012 - July 31, 2014
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Heraldo Possolo de Souza
• Grantee: Heraldo Possolo de Souza
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Denise Frediani Barbeiro ; Fabiano Pinheiro da Silva ; Thais Martins de Lima Salgado

Abstract

The family of transcriptional coactivators PGC-1 comprises three members (PGC-1±, PGC-1² and PRC), with extensive homology, but with different functions and expression patterns. Their main function is related to mitochondrial biogenesis and function. Moreover, they play key roles in controlling energy homeostasis, including hepatic gluconeogenesis, lipoprotein metabolism, thermogenesis, circadian clock and angiogenesis.More recently, broader functions for PGC-1s have been identified, suggesting its participation in cell death and proliferation as well as the adaptation of cells to stress conditions. The function of PGC-1 in inflammatory diseases, however, is still poorly known. The most important findings in this regard show the crucial role played by PGC-1² in macrophage polarization. This coactivator is responsible for driving macrophages to a reparative response (Th2), using fatty acids as energy substrate and increasing collagen production and anti-inflammatory cytokines secretion.In recent years, in our laboratory, we have devoted efforts to elucidate the role of these proteins in inflammatory and proliferative process.In a recent study (# FAPESP 2009-01990-9), we demonstrated that phagocytosis in macrophages depends on an adequate signaling through PGC-1±. Thus, based on recent findings from the literature and preliminary data from our laboratory, we have, as General Objective of this Project, evaluate the functions and mechanisms of action of transcription coactivators PGC-1 in different experimental models of inflammation. This objective will be pursued in three subprojects with different specific objectives: A) To determine whether the mRNA expression for PGC-1 ± and ² in leukocytes obtained from ascites of patients with liver disease may serve as a clinical indicator of infection.Strategy: There is currently a rapid and specific test to determine if the ascitic fluid of cirrhotic patients has bacterial infection. Our goal is to determine whether there is a positive correlation between the expression of mRNA for PGC-1 ± and ² in leukocytes obtained from the ascitic fluid of patients with liver disease. B) Determine the modulating effect of low intensity laser therapy (LLLI) in the transition inflammation-repair model of acute lung injury in mice. Strategy: LLLI appears to act positively in tissue repair. Considering the important role of PGC-1² in the polarization of macrophages, we hypothesized that LLLI may induce tissue repair by modulating the expression of PGC-1². We will test this hypothesis in a model of acute lung injury in mice undergoing or not the LLLI. C) Role of coactivators PGC-1 family in the remodeling of extracellular matrix. Strategy: depends on tissue remodeling processes (synthesis and degradation of extracellular matrix by MMPs) that may be influenced by metabolic state and redox cell. Since the family of coactivators PGC-1 control cell energy homeostasis, we hypothesized that they may also influence the tissue remodeling. We will test this hypothesis in cultured fibroblasts, where it is manipulated the expression of PGC-1 and skin samples from patients with different degrees of remodeling skin (controls, rigid skin of patients who suffered severe burns and loose skin of patients who lost weight after bariatric surgery). (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)

BARROSO, WERMERSON ASSUNCAO; VICTORINO, VANESSA JACOB; JEREMIAS, ISABELA CASAGRANDE; PETRONI, RICARDO COSTA; KUBO ARIGA, SUELY KUNIMI; SALLES, THIAGO A.; BARBEIRO, DENISE FREDIANI; DE LIMA, THAIS MARTINS; DE SOUZA, HERALDO POSSOLO. High-fat diet inhibits PGC-1 alpha suppressive effect on NF kappa B signaling in hepatocytes. EUROPEAN JOURNAL OF NUTRITION, v. 57, n. 5, p. 1891-1900, AUG 2018. (12/07957-6)