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

doi:10.1016/j.isci.2020.101763

Regulation of Gluconeogenesis by Aldo-keto-reductase 1a1b in Zebrafish

iScience. 2020 Nov 3;23(12):101763. doi: 10.1016/j.isci.2020.101763. eCollection 2020 Dec 18.

Authors

Affiliations

¹ Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany.
² Metabolomics Core Technology Platform, Centre for Organismal Studies, Heidelberg University, Heidelberg 69120, Germany.
³ Tissue Bank of the National Center for Tumor Diseases (NCT), Heidelberg 69120, Germany.
⁴ CMCP - Center for Model System and Comparative Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg 69120, Germany.
⁵ Electron Microscopy Lab, Institute of Pathology, University Hospital Heidelberg, Heidelberg 69120, Germany.
⁶ Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Heidelberg 69120, Germany.
⁷ German Center for Diabetes Research (DZD), München-Neuherberg 85764, Germany.
⁸ Joint Heidelberg-IDC Translational Diabetes Program, Helmholtz-Zentrum, München, Heidelberg 69120, Germany.

Abstract

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.

Keywords: Human Metabolism; Molecular Genetics.