Steroid 21-hydroxylase deficiency dysregulates essential molecular pathways of metabolism and energy provision

The prevalence of metabolic disease is increased in congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. However, the underlying molecular mechanisms causing these problems are not fully understood. We aimed to elucidate the metabolic phenotype and conduct a transcriptomic analysis of a 21-hydroxylase-deficient zebrafish model, to unravel the molecular mechanisms underlying the metabolic pathophysiology of CAH. The morphology, anatomy and transcriptomic analysis of whole larvae, adult liver tissue from 18-month-old cyp21a2-/- zebrafish were compared to those of wild-type siblings. Our main phenotypical finding was that adult mutants were larger, with increased fat deposition compared to controls, in-keeping with the transcriptomic analysis showing the dysregulation of several biological processes involved in lipid metabolism. Importantly, we found that ATP synthesis and provision of energy precursors were included among the most significantly suppressed processes in both larvae and adult livers. We conclude that cortisol deficiency in cyp21a2-/- mutants causes growth and body fat abnormalities at adult stages, as well as transcriptomic dysregulation of metabolic processes, energy homeostasis and inflammatory responses in both larvae and adults. These findings reveal how GC deficiency in zebrafish contributes to the development of the metabolic comorbidities that are similar to those observed in patients with CAH.