Lipid antigens as metabolic regulators of inflammation in non-alcoholic fatty liver disease

• Applicant: Professor Dr. Sebastian Zeissig
• Subject Area: Gastroenterology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 329658657

Obesity shows a rising incidence worldwide and is associated with inflammatory and malignant complications. Non-alcoholic fatty liver disease (NAFLD) is a common hepatic disorder associated with obesity and characterized by hepatocellular lipid accumulation. While NAFLD often shows a benign course of disease, hepatic steatosis can progress to an inflammatory state termed nonalcoholic steatohepatitis (NASH), which represents a risk factor for hepatic fibrosis and cirrhosis. Centrally involved in this process are natural killer T (NKT) cells, a subgroup of T cells which recognize lipid antigens in the context of the atypical MHC class I protein CD1d. However, while the role of NKT cells in the progression of NASH has been extensively characterized, the molecular nature of the antigens involved in NKT cell activation as well as their cellular origin remains unknown. Recent work has revealed that progression from steatosis to steatohepatitis in NAFLD is associated with increased hepatic abundance of lysophospholipids. Furthermore, we could demonstrate that CD1d-restricted presentation of lysophospholipids by hepatocytes is associated with the activation of hepatic NKT cells. We therefore propose to investigate whether metabolic alterations in NAFLD promote NKT cell-dependent inflammation in steatohepatitis through the generation of CD1d-associated lipid antigens. Given that CD1d is widely expressed among hepatic antigen presenting cells (APCs), we propose to first identify the APCs responsible for CD1d- and NKT cell-mediated hepatic inflammation in NASH using mice with conditional, cell-specific deletion of CD1d. Second, using human tissues and mice engineered to express a surface-cleavable form of CD1d, we propose to characterize, for the first time, the spectrum of lipids associated with hepatic CD1d in vivo and to identify alterations in the repertoire of CD1d-associated lipids that contribute to NKT cell-dependent progression of NAFLD. Third, we propose to investigate whether targeting of metabolic pathways involved in the generation of lipid antigens can inhibit NKT cell activation and NKT cell-mediated inflammation in NASH. These studies will provide novel insight into the mechanisms of metabolic control of immunity and shall contribute to the development of therapeutic strategies which target lipid antigen presentation at the origin of NKT cell-dependent inflammation in NASH.

• DFG Programme: Research Grants