Role of post-translational modification of TSC22D4 in the progression of non-alcoholic fatty liver disease

• Applicant: Bilgen Ekim, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 551373927

Recently we identified hepatic TSC22D4 as a critical controller of diabetic hyperglycemia and insulin resistance. Mechanistically, TSC22D4 interacts with Akt kinase to control insulin sensitivity and glucose tolerance. In the follow-up studies, we showed that obese patients with NAFLD and NASH have elevated TSC22D4 expression, positively correlating with liver disease progression. Our functional studies with TSC22D4 hepatocyte specific (TSC22D4hepKO) knock out mice indicated that TSC22D4 has a causal role in excessive lipid accumulation, inflammation, apoptosis in the liver causing NAFLD and NASH-related pathologies by impairing mitochondrial function. Interestingly, the role of TSC22D4 in progression of liver disease is not restricted to the hepatocytes but is also evident in hepatic stellate cells (HSCs), where TSC22D4 acts downstream of TGFß1 signaling to promote the expression of HSC activation markers α-smooth muscle actin (alpha-SMA), Smad3, and collagen, type I, alpha 1 (Col1a1) and contributes to cell proliferation and migration. In contrast to defined downstream functions of TSC22D4 in the liver, we know very little of its upstream regulators. Hence, the overarching objective of this proposal is the establishment of a novel layer of metabolic control. Specifically, the major objective of this study aims to elucidate the functional role of post-translational modification of TSC22D4 in the control of its function and the progression of NAFLD and NASH. To this end, Germany located-PI (GPI) will focus on the putative Ser/Thr kinase machinery that is directly responsible for TSC22D4 phosphorylation. In addition, GPI group will delineate the functional consequences of TSC22D4 phosphorylation on liver physiology and the progression of NAFLD and NASH. Korea-located PI (KPI) group will focus on the impact of arginine methylation of TSC22D4 in the control of its activity and its relation to the health of liver. This study would not be able take place without the cooperation between KPI and GPI as it combines two different areas of expertise i.e. arginine methylation and Ser/Thr phosphorylation together and provides a unique setting to study the regulation and function of TSC22D4 in liver disease. Ultimately, we would like to elucidate the intricate regulatory mechanism for controlling TSC22D4 function that will be helpful in the potential development of a novel therapeutic approach for the treatment of NAFLD/NASH.

• DFG Programme: Research Grants
• International Connection: South Korea
• Partner Organisation: National Research Foundation of Korea, NRF
• Cooperation Partner: Professor Dr. Seung-Hoi Koo