Investigating the role of TCF7L2 in hepatic metabolism

• Applicant: Dr. Mareike Schell
• Subject Area: Anatomy and Physiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 540879521

The prevalence of diabetes and associated comorbidities, such as non-alcoholic fatty liver disease (NAFLD), is constantly rising. Therefore, the development of novel preventive and therapeutic strategies is urgently needed. Many of our insights into disease development derive from large-scale human studies, which have successfully identified several causal associations between genetic variants and metabolic parameters. TCF7L2, 'the diabetes gene', was already identified in 2006 and associates not only with an increased risk for diabetes but also for NAFLD. However, its functional role, especially in the liver, remains inconclusive. The goal of this proposal is the investigation of the role of TCF7L2 in liver metabolism. Unpublished preliminary data from the host lab have shown that a hepatocyte-TCF7L2 deletion (knock-out, KO) does not alter glucose metabolism but instead, re-models hepatic lipid distribution, resulting in a more uniform lipid accumulation in TCF7L2-KO mice compared to a pericentral accumulation in control mice. This suggest, in combination with single nucleus RNA sequencing analysis, that TCF7L2 signaling is not uniformly expressed in the liver and disruption of TCF7L2 disturbs region-specific organization of metabolism. Two examples will be analyzed in this proposal. Firstly, it has been shown that mitochondria within the liver differ depending on their location within hepatocytes across the lobule, suggesting that TCF7L2-KO may disrupt mitochondrial organization and thereby metabolism. Mitochondrial dysfunction already been associated with NAFLD and TCF7L2-KO may lead to a maladaptation of mitochondrial metabolism leading to differences in lipid accumulation. Secondly, own preliminary gene expression analyses in the host lab have shown that the two main metformin transporters in the liver OCT1 and OCT3 were robustly decreased in TCF7L2 KO mice, which may cause a resistance to metformin and thereby inhibit metformin's positive effects on liver metabolism such as a decrease in lipid accumulation.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Dr. Sudha Biddinger