Hepatic inflammation: role of inflammatory cell infiltration, adipose tissue xpansion/inflammation and TRL activation

• Grant number: 11/13710-0
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2012
• End date: July 31, 2014
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Alessandra Gambero
• Grantee: Alessandra Gambero
• Host Institution: Pró-Reitoria Acadêmica. Universidade São Francisco (USF). Campus Bragança Paulista. Bragança Paulista , SP, Brazil

Abstract

Nonalcoholic steatohepatitis (NASH) is an inflammatory disease associated to liver fat accumulation. NASH is associated with obesity but the pathogenesis is not fully understood. The "Two hit theory" postulated that the first injury is the steatosis due adipose tissue insulin resistance and free fatty acid level increase. The second "hit" occurs by oxygen reactive species (ROS) production that stimulated hepatocytes to produce pro-inflammatory cytokines, and, induces leukocyte migration and liver fibrosis. The immune cell migration to liver acts as an important factor for pathology progression. Macrophages, monocytes and neutrophils are attracted and contribute to liver inflammation. Monocytes are also attracted to adipose tissue and they have a role in the pro-inflammatory adipocytokine production and NASH establishment. Although the adipose tissue is considered an important factor in NASH establishment, LPS (a TLR agonist) could also be important. The therapeutic approaches to NASH patients are not perfect and more studies are needed. The aim of this study is to evaluate the immune cell infiltration to the liver in two experimental models: high-fat diet induced-obesity and fructose rich diet induced-NASH, searching for the understanding of the migration kinetic and the possible role of these cells in the establishment of NASH and metabolic alterations. We also intend to understand the interactions of liver cells, using the co-culture system of macrophage/ hepatocyte in vitro, as well as, the role of TLRs receptors in these cells. And finally, we intend to contribute with a better understanding the activity of anti-oxidant substances as protective in NASH. (AU)