摘要：SummaryRegulation 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. Adultakr1a1b−/−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-hpfakr1a1b−/−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 inakr1a1b−/−mutants. Thus, the data have identified Akr1a1b as a regulator of gluconeogenesis in zebrafish and thereby controlling glucose homeostasis.Graphical AbstractDisplay OmittedHighlights•Adultakr1a1b−/−mutant zebrafish develop fasting hypoglycemia•Loss of Akr1a1b inhibits renal phosphoenolpyruvate carboxykinase (PEPCK) expression•Accumulation of glucogenic amino acid glutamate alters the kidney inakr1a1bmutants•Akr1a1b regulates gluconeogenesis via protein-S-nitrosylationHuman Metabolism; Molecular Genetics
