CD1d as direct, Natural Killer T cell-independent regulator of hepatic lipid metabolism and metabolic dysfunction-associated steatotic liver disease

• Applicant: Professor Dr. Sebastian Zeissig
• Subject Area: Gastroenterology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 554076041

CD1d is an atypical MHC class I protein which binds self- and non-self-derived lipids and activates a subset of lipid-reactive T cells termed natural killer T (NKT) cells through antigen presentation. NKT cells are an abundant immune cell population in the liver with critical roles in antimicrobial immunity, autoimmunity, and metabolic dysfunction-associated steatotic liver disease (MASLD). Studies on the function of CD1d in these processes have exclusively focused on the role of CD1d in the interaction with NKT cells. However, CD1d is abundantly expressed by hepatocytes and binds a wide spectrum of endogenous cellular glycerophospholipids and sphingolipids, suggesting that CD1d may also directly affect hepatic lipid metabolism and MASLD progression in a manner independent of NKT cells. Consistent with this notion, we have demonstrated in preliminary studies that CD1d promotes hepatic neutral lipid accumulation, steatosis and progression of MASLD in an NKT cell-independent manner. These findings highlight CD1d as a novel direct regulator of hepatic lipid metabolism and MASLD, and as a potential therapeutic target. In this proposal, we therefore aim to: 1. Delineate cell-autonomous and non-cell autonomous contributions of CD1d in the regulation of hepatocyte lipid metabolism and MASLD. 2. Characterize the molecular mechanisms through which CD1d regulates hepatic lipid metabolism. 3. Investigate whether therapeutic targeting of CD1d provides efficacy in mouse models of MASLD and study the role of CD1d in human hepatic lipid metabolism. Our studies are the first to address direct, NKT cell-independent effects of CD1d in the liver, will characterize the role of CD1d as direct regulator of hepatic lipid metabolism, and will reveal whether therapeutic targeting of CD1d can provide efficacy in the treatment of MASLD in preclinical mouse models.

• DFG Programme: Research Grants