Kupffer cells in high fat diet-induced insulin resistance

Kupffer cells are re-emerging as a critical mediator of liver injury. While the role of Kupffer cells in alcoholic liver disease has been well studied, there is a growing appreciation that Kupffer cells are also critical to the development of hepatic insulin resistance, as well nonalcoholic fatty liver disease (NAFLD) in obesity and metabolic syndrome. NAFLD is a spectrum of disorders that include steatosis, steatosis with inflammation, nonalcoholic steatohepatitis (NASH) and NASH with fibrosis. Advanced NAFLD, particularly NASH with fibrosis, is a considerable risk for progression into cirrhosis and hepatocellular cancer. Because of its high prevalence, NAFLD may surpass chronic hepatitis C as the leading indication for liver transplant by 2020. Kupffer cells are the resident macrophages in the liver. Kupffer cells exhibit a tremendous plasticity: depending on the local metabolic and immune environment, Kupffer cells can exhibit a range of polarized phenotypes, ranging from a pro-inflammatory M1 phenotype to an alternative/M2 phenotype. Multiple M2 phenotypes can be distinguished, each involved in the resolution of inflammation and wound healing. The goal of this symposium is to provide an update from basic research on developing perspectives for contribution of Kupffer cells to NAFLD/NASH and new insights into the potential for therapeutic manipulation of Kupffer cells to promote the resolution of inflammation and enhance wound healing in liver disease. Course objectives and goals • Appreciate the phenotypic plasticity of tissue resident macrophages • Understand the interactions between Kupffer cells and metabolic activity in hepatocytes • Describe the role of Kuppfer cells in animal models of NAFLD • Discuss potential therapeutic implications of Kupffer cell plasticit