Molecular insight into steroid hormone synthesis
Steroid hormones such as oestradiol and testosterone are derived from cholesterol mainly in the adrenal gland and gonads. They have a central role in sex development, metabolism, blood pressure and body composition, and their synthesis is conserved among species. Accumulating evidence underscores the importance of cofactors in the function of steroidogenic enzymes. The EU-funded MISTRAL (Mitochondrial steroidogenesis in the adrenal) project wished to identify key genes implicated in steroidogenesis in vivo. They deleted various genes with putative steroidogenic function in zebrafish to investigate their role during embryonic development as well as adult life. Among the genes that generated interesting observations was the mammalian homologue FDX1, which encodes a small iron-sulphur protein implicated in bile acid and vitamin D synthesis. Researchers discovered that mutant embryos were darker due to a failure in the cortisol-mediated pigmentation pathway known as visual background adaptation behaviour. A similar phenotype could be seen in patients suffering from the endocrine disorder Addison's. In addition, FDX1 deletion greatly impacted stress response and cortisol synthesis. From a molecular perspective, FDX1 deficiency was associated with genes implicated in metabolism and metabolic disorders, similarly to what is seen in patients suffering from adrenal insufficiency. Insight into the impaired metabolic pathways unveiled a role for genes involved in biomolecule synthesis, energy production and oxidative stress response. The results of this transcription analysis were validated through metabolic profiling using NMR and mass spectrometry. Furthermore, scientists made a significant observation regarding the expression of FDX1 in the adult zebrafish brain alongside several steroidogenic genes. Collectively, the findings of the MISTRAL study suggest a connection between steroid hormone synthesis and metabolism. The molecular players in this axis will undoubtedly serve as targets for the design of future treatments against adrenal insufficiency.
Keywords
Steroid hormone, metabolism, MISTRAL, FDX1, oxidative stress
