Novel functions of Retinol Saturase in glucose sensing

• Applicant: Professor Michael Schupp, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism ; Pharmacology ; Cell Biology
• Term: from 2018 to 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 415542650

• Final Report Year: 2025

Final Report Abstract

Retinol Saturase (RetSat) is an oxidoreductase localized in the endoplasmic reticulum and highly expressed in metabolically active organs like liver, intestine, and adipose tissue. Although initially implicated in the synthesis of 13,14-dihydroretinol, RetSat likely convers other yet unknown enzymatic reactions. This project analyzed tissue-specific functions of RetSat in novel genetic mouse models and human tissue samples. We found that RetSat expression is under β-adrenergic control in adipocytes and determines thermogenic capacity of brown adipocytes and acute cold tolerance in mice. RetSat expression in subcutaneous white adipose tissue of humans correlates with the expression of genes related to mitochondrial function. In regard to the underlying mechanism, we found that RetSat depletion in adipocytes impaired βagonist-induced lipolysis, which represents a major determinant of thermogenic gene expression in these cells. In the intestine, RetSat localizes to intestinal epithelial cells and its deletion decreased weight gain and fat mass in obese mice. In colitis, which downregulated intestinal RetSat expression in humans and mice, RetSat ablation improved the epithelial architecture of the murine colon, potentially by reducing the production of reactive oxygen species. Finally, we found that a hepatocyte-specific RetSat deletion in mice did not alter the concentration of retinol and 13,14-dihydroretinol in liver tissue, suggesting that its enzymatic activity and cellular functions are independent of vitamin A. These insights will help to develop RetSat as novel pharmacologic target for metabolic diseases.

Publications

• Enzymatic activity of Retinol Saturase is required for its oxidative stress response (Posterpräsentation, 2019 Nature Conference on Cellular Metabolism, Xiamen, China)
  Pamela Weber
  
• Retinol Saturase: More than the Name Suggests. Trends in Pharmacological Sciences, 41(6), 418-427.
  Weber, Pamela; Flores, Roberto E.; Kiefer, Marie F. & Schupp, Michael
  
• The glucose-sensing transcription factor ChREBP is targeted by proline hydroxylation. Journal of Biological Chemistry, 295(50), 17158-17168.
  Heidenreich, Steffi; Weber, Pamela; Stephanowitz, Heike; Petricek, Konstantin M.; Schütte, Till; Oster, Moritz; Salo, Antti M.; Knauer, Miriam; Goehring, Isabel; Yang, Na; Witte, Nicole; Schumann, Anne; Sommerfeld, Manuela; Muenzner, Matthias; Myllyharju, Johanna; Krause, Eberhard & Schupp, Michael
  
• Intestine-Specific Deletion of Retinol Saturase Reduces Adiposity in Mice (Posterpresentation, 2022 Leipzig Lipid Meeting (online))
  Marie F. Kiefer
  
• Retinol Saturase expression in brown adipose tissue is induced by cold exposure and indispensable for acute thermoregulation in mice (Posterpräsentation, 2022 The heterogeneity and plasticity of adipose tissue CPH BAT Conference, Kopenhagen, Dänemark)
  Chen Li
  
• Sugar-responsive inhibition of Myc-dependent ribosome biogenesis by Clockwork orange. Cell Reports, 42(7), 112739.
  van den Berg, Linda; Kokki, Krista; Wowro, Sylvia J.; Petricek, Konstantin M.; Deniz, Onur; Stegmann, Catrin A.; Robciuc, Marius; Teesalu, Mari; Melvin, Richard G.; Nieminen, Anni I.; Schupp, Michael & Hietakangas, Ville
  
• The role of Retinol Saturase in the modulation of endoplasmic reticulum stress (Vortrag, 2023 Leipzig Lipid Meeting)
  Jonah W. Schreier
  
• Adipose retinol saturase is regulated by β-adrenergic signaling and its deletion impairs lipolysis in adipocytes and acute cold tolerance in mice. Molecular Metabolism, 79, 101855.
  Li, Chen; Kiefer, Marie F.; Dittrich, Sarah; Flores, Roberto E.; Meng, Yueming; Yang, Na; Wulff, Sascha; Gohlke, Sabrina; Sommerfeld, Manuela; Wowro, Sylvia J.; Petricek, Konstantin M.; Dürbeck, Dominic; Spranger, Leonard; Mai, Knut; Scholz, Holger; Schulz, Tim J. & Schupp, Michael
  
• Intestinal retinol saturase is implicated in the development of obesity and epithelial homeostasis upon injury. American Journal of Physiology-Endocrinology and Metabolism, 327(2), E203-E216.
  Kiefer, Marie F.; Meng, Yueming; Yang, Na; Vahrenbrink, Madita; Wulff, Sascha; Li, Chen; Wowro, Sylvia J.; Petricek, Konstantin M.; Sommerfeld, Manuela; Flores, Roberto E.; Obermayer, Benedikt; Piepelow, Karolin; Klaus, Susanne; Hartl, Kimberly; Guillot, Adrien; Tacke, Frank; Sigal, Michael & Schupp, Michael
  
• p53 terminates the regenerative fetal-like state after colitis-associated injury. Science Advances, 10(43).
  Hartl, Kimberly; Bayram, Şafak; Wetzel, Alexandra; Harnack, Christine; Lin, Manqiang; Fischer, Anne-Sophie; Liu, Lichao; Beccaceci, Giulia; Mastrobuoni, Guido; Geisberger, Sabrina; Forbes, Martin; Monteiro, Benedict J. E.; Macino, Martina; Flores, Roberto E.; Engelmann, Cornelius; Mollenkopf, Hans-Joachim; Schupp, Michael; Tacke, Frank; Sanders, Ashley D. ... & Sigal, Michael