Serpina6, encoding corticosteroid-binding globulin (CBG), is a crucial gene. CBG transports glucocorticoids in the blood, regulating their plasma distribution, access to cells, and thus influencing glucocorticoid-related actions [1,2]. Glucocorticoids control hepatic development, metabolic activities, and adrenal development, highlighting the importance of Serpina6 in these biological processes. Genetic models, such as gene-knockout (KO) models, are valuable for studying Serpina6.

In rat KO models, disruption of the SerpinA6 gene led to several findings. In the liver, CBG deficiency limited corticosterone clearance by reducing its hepatic uptake. In 60-day-old rats, ∼10% of genes with sexually dimorphic expression in wild-type female livers lost this characteristic in females lacking CBG, affecting processes like cholesterol biosynthesis, inflammation, and lipid and amino acid catabolism. Another 203 genes were specifically altered in adult females lacking CBG, related to xenobiotic metabolism, circadian rhythm, and gluconeogenesis [1]. In the adrenal gland, the absence of CBG led to a ∼80% reduction in total plasma corticosterone levels in adult rats of both sexes, with a greater reduction in females. The sex-specific differences in adrenal growth, morphology, and gene expression that emerge during puberty in rats were lost in rats without CBG [2].

In conclusion, Serpina6 is essential for regulating glucocorticoid-related processes in the liver and adrenal gland. Gene-knockout models of Serpina6 in rats have revealed its role in establishing sexual dimorphism in the liver and adrenal development, providing insights into how CBG deficiencies may be linked to glucocorticoid-dependent diseases [1,2].