The role of subcellular vitamin E deficiency and the α-tocopherol transfer protein in non-alcoholic fatty liver disease

• Applicant: Dr. Maren Catherina Podszun
• Subject Area: Nutritional Sciences
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 466412114

Non-alcoholic fatty liver disease (NAFLD), a disease characterized by excessive accumulation of hepatic lipids, is becoming the most common liver disorder in the Western world. Currently, there are no EMA approved treatments for NAFLD and the lipid soluble vitamin E, specifically alpha tocopherol (αT), has been investigated as a potential treatment. Increased accumulation of hepatic fat as lipid droplets is believed to lead to increased oxidative stress, especially lipid peroxidation. αT is a fat-soluble antioxidant and there is currently evidence to suggest that it is sequestered in lipid droplets depleting other organelles of αT, possibly increasing oxidative stress locally. The expression of the intracellular vitamin E trafficking protein, alpha tocopherol transfer protein (αTTP) is decreased in NAFLD whereas its role in trafficking αT to lipid droplets is currently unknown. The overall goal of this project is to identify the impact of lipid droplets on subcellular distribution of αT and the role of αTTP. To this end, subcellular distribution of αT will be investigated in cells with and without the expression of αTTP in the absence and presence of lipid droplets. Findings will be validated in primary mouse hepatocytes, isolated from homo- and heterozygous αTTP knockout mice and their wildtype controls. The impact of αTTP on αT accumulation in lipid droplets as well as on steatosis will be evaluated in the aforementioned mouse model fed an obesogenic diet. Lastly, vitamin E and triglycerides in human liver samples from NAFLD patients and controls will be analyzed to investigate a potential/possible correlation between triglyceride content and αT, providing further support to the notion that increased lipid storage increases αT sequestration, possibly leading to subcellular vitamin E deficency. This proposal will identify the effect of lipid droplets on the subcellular distribution of vitamin E as well as the role of the α-tocopherol transfer protein (αTTP) in the context of non-alcoholic fatty liver disease (NAFLD). Furthermore, the results of this project will show if αTTP is a promising novel therapeutic target for the treatment of NAFLD.

• DFG Programme: Research Grants
• International Connection: USA
• Co-Investigator: Professor Dr. Jan Frank, Ph.D.
• Cooperation Partner: Dr. Yaron Rotman