Control of the cellular sugar sensor ChREBP by proline hydroxylases and hypoxia

• Applicant: Professor Michael Schupp, Ph.D., since 1/2024
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 502067018

The liver is a pivotal relay in carbohydrates and lipid metabolism. Aberrant lipid accumulation results in hepatic steatosis, which, although per se non-pathological, is commonly observed in obese patients and can lead to non-alcoholic fatty liver disease (NAFLD). Although the underlying causes for the pathological accumulation of hepatic lipids can be multifactorial, dysregulated sugar sensing, de novo lipogenesis, and fatty acid desaturation appear to be central to the development of NAFLD. We have previously identified a novel post-translational modification (PTM) of the glucose metabolite-sensing transcription factor carbohydrate response element-binding protein (ChREBP), a protein that controls hepatic gene expression of glycolytic and lipogenic pathways. ChREBP protein is proline hydroxylated at several residues, physically interacts with known proline hydroxylases, and mutating these proline residues impairs the activation of ChREBP by glucose in vitro. We therefore hypothesize that proline hydroxylation of hepatic ChREBP is implicated in the development of NAFLD. This proposal will address the regulation of ChREBP by proline hydroxylases in the context of fatty liver disease. Since proline hydroxylases require oxygen for their enzymatic activity, we will also analyze whether low oxygen pressure, known to occur in liver tissue surrounding the central vein and contributing to the characteristic liver zonation, affects the expression and activity of ChREBP via alterations in proline hydroxylation. Thus, we define three objective in order to 1) identify and characterize novel hydroxylated proline residues of ChREBP and whether or not they are dynamically regulated in fatty liver and conserved in human hepatocytes, to 2) elucidate the molecular interactions of oxygen-sensing pathways and ChREBP, and to 3) investigate whether genetic deletion or pharmacological inhibition of proline hydroxylases in mice affects ChREBP responses and the development of fatty liver upon dietary challenges. This project may identify novel therapeutic strategies to combat metabolic liver diseases like NAFLD.

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Dr. Sylvia Justina Wowro, until 1/2024