Regulation of Gluconeogenesis by Aldo-keto-reductase 1a1b in Zebrafish
Xiaogang Li,
Felix Schmöhl,
Haozhe Qi,
Katrin Bennewitz,
Christoph T. Tabler,
Gernot Poschet,
Rüdiger Hell,
Nadine Volk,
Tanja Poth,
Ingrid Hausser,
Jakob Morgenstern,
Thomas Fleming,
Peter Paul Nawroth,
Jens Kroll
Affiliations
Xiaogang Li
Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany
Felix Schmöhl
Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany
Haozhe Qi
Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany
Katrin Bennewitz
Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany
Christoph T. Tabler
Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany
Gernot Poschet
Metabolomics Core Technology Platform, Centre for Organismal Studies, Heidelberg University, Heidelberg 69120, Germany
Rüdiger Hell
Metabolomics Core Technology Platform, Centre for Organismal Studies, Heidelberg University, Heidelberg 69120, Germany
Nadine Volk
Tissue Bank of the National Center for Tumor Diseases (NCT), Heidelberg 69120, Germany
Tanja Poth
CMCP - Center for Model System and Comparative Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg 69120, Germany
Ingrid Hausser
Electron Microscopy Lab, Institute of Pathology, University Hospital Heidelberg, Heidelberg 69120, Germany
Jakob Morgenstern
Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Heidelberg 69120, Germany
Thomas Fleming
Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Heidelberg 69120, Germany
Peter Paul Nawroth
Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Heidelberg 69120, Germany; German Center for Diabetes Research (DZD), München-Neuherberg 85764, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Helmholtz-Zentrum, München, Heidelberg 69120, Germany
Jens Kroll
Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany; Corresponding author
Summary: Regulation of glucose homeostasis is a fundamental process to maintain blood glucose at a physiological level, and its dysregulation is associated with the development of several metabolic diseases. Here, we report on a zebrafish mutant for Aldo-keto-reductase 1a1b (akr1a1b) as a regulator of gluconeogenesis. Adult akr1a1b−/− mutant zebrafish developed fasting hypoglycemia, which was caused by inhibiting phosphoenolpyruvate carboxykinase (PEPCK) expression as rate-limiting enzyme of gluconeogenesis. Subsequently, glucogenic amino acid glutamate as substrate for gluconeogenesis accumulated in the kidneys, but not in livers, and induced structural and functional pronephros alterations in 48-hpf akr1a1b−/− embryos. Akr1a1b−/− mutants displayed increased nitrosative stress as indicated by increased nitrotyrosine, and increased protein-S-nitrosylation. Inhibition of nitrosative stress using the NO synthase inhibitor L-NAME prevented kidney damage and normalized PEPCK expression in akr1a1b−/− mutants. Thus, the data have identified Akr1a1b as a regulator of gluconeogenesis in zebrafish and thereby controlling glucose homeostasis.
