Regulierung des hepatischen Glukose- und Fettstoffwechsels durch die Retinol Saturase

• Antragsteller: Professor Michael Schupp, Ph.D.
• Fachliche Zuordnung: Endokrinologie, Diabetologie, Metabolismus
• Förderung: Förderung von 2010 bis 2017
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 161885875

• Erstellungsjahr: 2017

Zusammenfassung der Projektergebnisse

The liver integrates multiple metabolic pathways to warrant systemic energy homeostasis. An exaggerated lipogenic flux due to chronic dietary stimulation contributes to the development of hepatic steatosis, dyslipidemia, and hyperglycemia. We identified a novel function of the oxidoreductase retinol saturase (RetSat) in metabolic liver disease. Hepatic RetSat expression correlated with steatosis and serum triglycerides in humans. Liver-specific disruption of RetSat in dietary-obese mice lowered hepatic and circulating triglycerides and normalized hyperglycemia. Mechanistically, RetSat depletion reduced the activity of carbohydrate response element-binding protein (ChREBP), a cellular hexose-phosphate sensor and inducer of de novo lipogenesis. Defects upon RetSat depletion were rescued by ectopic ChREBP but not by its putative enzymatic product 13,14-dihydroretinol, suggesting that RetSat affects hepatic glucose sensing independent of retinol conversion. In summary, we identified RetSat as critical regulator of liver metabolism that functions upstream of ChREBP. Pharmacologic inhibition of RetSat in liver may represent a therapeutic approach to metabolic liver disease.

Projektbezogene Publikationen (Auswahl)

• Endogenous ligands for nuclear receptors: digging deeper. J Biol Chem 2010. 285(52):40409-40415
  Schupp, M. and M. A. Lazar
  
• Histone deacetylase 6 (HDAC6) is an essential modifier of glucocorticoidinduced hepatic gluconeogenesis. Diabetes 2012. 61(2):513-523
  Winkler, R., V. Benz, M. Clemenz, M. Bloch, A. Foryst-Ludwig, S. Wardat, N. Witte, M. Trappiel, P. Namsolleck, K. Mai, J. Spranger, G. Matthias, T. Roloff, O. Truee, K. Kappert, M. Schupp, P. Matthias and U. Kintscher
  
• The GTPase ARFRP1 is essential for normal hepatic glycogen storage and IGF1 secretion. Mol Cell Biol 2012. 32(21):4363-74
  Hesse, D., A. Jaschke, T. Kanzleiter, N. Witte, R. Augustin, A. Hommel, G. P. Puschel, K. J. Petzke, H. G. Joost, M. Schupp and A. Schurmann
  
• Metabolite and transcriptome analysis during fasting suggest a role for the p53-Ddit4 axis in major metabolic tissues. BMC Genomics, 2013. 14(1):758
  Schupp, M., F. Chen, E. R. Briggs, S. Rao, H. J. Pelzmann, A. R. Pessentheiner, J. G. Bogner- Strauss, M. A. Lazar, D. Baldwin and A. Prokesch
  
• Retinol-binding protein 4 and its membrane receptor STRA6 control adipogenesis by regulating cellular retinoid homeostasis and retinoic acid receptor alpha activity. Mol Cell Biol 2013. 33(20):4068-4082
  Muenzner, M., N. Tuvia, C. Deutschmann, N. Witte, A. Tolkachov, A. Valai, A. Henze, L. E. Sander, J. Raila and M. Schupp
  
• The mammalian INDY homolog is induced by CREB in a rat model of type 2 diabetes. Diabetes 2014. 63(3):1048-1057
  Neuschafer-Rube, F., S. Lieske, M. Kuna, J. Henkel, R. J. Perry, D. M. Erion, D. Pesta, D. M. Willmes, S. Brachs, C. von Loeffelholz, A. Tolkachov, M. Schupp, A. Pathe-Neuschafer-Rube, A. F. Pfeiffer, G. I. Shulman, G. P. Puschel and A. L. Birkenfeld
  
• Retinol binding protein 4 and its membrane receptors: a metabolic perspective. Horm Mol Biol Clin Investig 2015. 22(1):27-37
  Fedders, R., M. Muenzner and M. Schupp
  
• The Glucose Sensor ChREBP Links De Novo Lipogenesis to PPARgamma Activity and Adipocyte Differentiation. Endocrinology 2015. 156(11):4008-4019
  Witte, N., M. Muenzner, J. Rietscher, M. Knauer, S. Heidenreich, A. M. Nuotio-Antar, F. A. Graef, R. Fedders, A. Tolkachov, I. Goehring and M. Schupp
  
• Liver p53 is stabilized upon starvation and required for amino acid catabolism and gluconeogenesis. FASEB J 2017, 31(2):732-742
  Prokesch A., Graef F.A., Madl T., Kahlhofer J., Heidenreich S., Schumann A., Moyschewitz E., Pristoynik P., Blaschitz A., Knauer M., Muenzner M., Bogner-Strauss J.G., Dohr G., Schulz T.J., Schupp M.
  
• Reciprocal regulation of carbon monoxide metabolism and the circadian clock. Nat Struct Mol Biol 2017, 24(1):15-22
  Klemz R., Reischl S., Wallach T., Witte N., Jürchott K., Klemz S., Lang V., Lorenzen S., Knauer M., Heidenreich S., Xu M., Ripperger J.A., Schupp M., Stanewsky R., Kramer A.
  
• Retinol Saturase Coordinates Liver Metabolism by Regulating ChREBP Activity. Nat Commun 2017, 8(1):384
  Heidenreich S., N. Witte, P. Weber, I. Goehring, A. Tolkachov, C. von Loeffelholz, S. Döcke, M. Bauer, M. Stockmann, A.F. Pfeiffer, A. L. Birkenfeld, M. Pietzke, S. Kempa, M. Muenzner, and Schupp M.