Pediatric non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in children, and can lead to liver fibrosis, cirrhosis and hepatocellular carcinoma. Nevertheless, an optimal diagnostic algorithm and pharmacological treatment options are currently lacking. Angiogenesis and macrophage-mediated inflammation are two interconnected mechanisms in adult NAFLD, but have not been studied in detail in pediatric disease. In this project, I aim to integrate fundamental and translational approaches to identify new targets in pediatric NAFLD.
Firstly, the potential for diagnosis by novel noninvasive markers will be explored in a large population of obese children and adolescents. A pilot study indicates the presence of NAFLD and even advanced liver fibrosis in obese children and adolescents with severe obesity, confirming the suitability of this large cohort. The inflammatory and transcriptomic repolarization in circulating monocytes in these patients will be elucidated, following data we obtained in adult NAFLD patients. Furhtermore, angiogenesis and macrophage subsets will be characterized in-depth in a murine NAFLD model. This will lay the groundwork for targeting the angiogenic-macrophage crosstalk via genetic and pharmacological inhibition of the chemokine receptor CXCR4, which plays pathogenic roles in both macrophages and endothelial cells.