Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in society, yet few drugs are available that specifically target this disease. Glucagon-like peptide-1 (GLP-1) mimetics were shown to alleviate pathology of non-alcoholic steatohepatitis (NASH), but the underlying mechanism is unknown. Here we aimed to identify mediators of inflammation in the context of NAFLD/NASH and investigate whether they can be targeted by dulaglutide.
Mice were fed with a diet (SSD) containing high amounts of fat, fructose and cholesterol to induce NASH. Histology was used to quantify liver pathology in animals. Genetically modified mice were used to demonstrate the specific role of immunological mediators in development of pathology. Animals were injected once weekly with dulaglutide or vector control to measure its impact on development of liver fibrosis and inflammation.
SSD-diet induced all stages of NAFLD/NASH, including fibrosis. SSD induced a strong increase of IL-17 producing γδ T cells in liver. δ-/- mice lacking γδ T cells, or animals with hepatocyte-specific deficiency for the IL-17 receptor showed a strong reduction in liver inflammation and fibrosis. We found that γδ T cells in liver expressed the receptor for GLP-1. Treatment of SSD-fed animals with dulaglutide impaired γδ T cell activation in liver and reduced fibrosis.
Hepatic stress in liver in the context of NAFLD activates γδ T cells. These cells start producing IL-17, which drives hepatic inflammation and fibrosis. Dulaglutide appears to impair γδ T cell activation and initiation of liver inflammation in the context of NAFLD/NASH.