Metabolic Liver Disease Research Projects

Role of Macrophage IFNy Signaling and IL-12 as Key Mediators of Intrahepatic Crosstalk Between Immune Cells and Hepatocytes in Obesity-Mediated Insulin Resistance and Metabolic Dysfunction-Associated Steatohepatitis

Obesity is a major cause of metabolic dysfunction-associated steatohepatitis (MASH) and is characterized by inflammation and insulin resistance. Interferon- g (IFN g ) is a pro-inflammatory cytokine elevated in obesity and modulating macrophage functions. Here, we show that male mice with loss of IFN  g signaling in myeloid cells (Lyz-IFNyR2-/-) are protected from diet-induced insulin resistance despite fatty liver. Obesity-mediated liver inflammation is also attenuated with reduced interleukin (IL)-12, a cytokine primarily released by macrophages, and IL-12 treatment in vivo causes insulin resistance by impairing hepatic insulin signaling. Following MASH diets, Lyz-IFNyR2-/- mice are rescued from developing liver fibrosis, which is associated with reduced FGF21 levels. These results indicate novel roles for IFN g signaling in macrophages and their release of IL-12 in modulating obesity-mediated insulin resistance and fatty liver progression to MASH. In this work, we identify the IFN-IL12 axis in regulating intercellular crosstalk in the liver and as potential therapeutic targets to treat MASH.