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Corticosteroid-binding globulin (SERPINA6) consolidates sexual dimorphism of adult rat liver

ABSTRACT: Produced by the liver, corticosteroid-binding globulin (CBG) regulates the plasma distribution and actions of glucocorticoids. A sex difference in pituitary growth hormone secretion patterns established during puberty in rats results in increased hepatic CBG production and two-fold higher plasma corticosterone levels in females. Glucocorticoids control hepatic development and metabolic activities, and we have therefore examined how disrupting the SerpinA6 gene encoding CBG influences plasma corticosterone dynamics, as well as liver gene expression in male and female rats before and after puberty. Comparisons of corticosterone plasma clearance and hepatic uptake in adult rats, with or without CBG, indicated that CBG limits corticosterone clearance by reducing its hepatic uptake. Hepatic transcriptomic profiling revealed minor sex differences (207 differentially expressed genes) and minimal effect of CBG deficiency in 30-day-old rats before puberty. While liver transcriptomes in 60-day-old males lacking CBG remained essentially unchanged, 2,710 genes were differentially expressed in wild-type female versus male livers at this age. Importantly, ~10% of these genes lost their sexually dimorphic expression in adult females lacking CBG, including those related to cholesterol biosynthesis, inflammation, and lipid and amino acid catabolism. Another 203 genes were altered by the loss of CBG specifically in adult females, including those related to xenobiotic metabolism, circadian rhythm, and gluconeogenesis. Our findings reveal that CBG consolidates the sexual dimorphism of the rat liver initiated by sex differences in growth hormone secretion patterns and provide insight into how CBG deficiencies are linked to glucocorticoid-dependent diseases.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE245348 | GEO | 2023/11/03

REPOSITORIES: GEO

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Project description:Intestinal paracellular permeability (IPP) is high at birth and is involved in gut barrier maturation and liver development. Chronic maternal separation (MS) in early life alters intestinal barrier function in adulthood. However, only transient MS commonly occurs in human newborns, but whether a single episode of MS in early postnatal days (PND) affects the maturation of the gut-liver axis has not been explored. The aim of the current study was to evaluate the effect of a single MS of short duration in neonate rats on epithelial barrier integrity in the gut and on gene expression in the liver. Male and female pups were separated from their dams for 4h or not (controls) at PND10 or PND20. Total intestinal paracellular permeability (IPP) was measured through mucosal-to-plasma passage of oral FITC-Dextran 4 KD with or without ML7, a blocker of myosin light chain kinase (MLCK), or Mifepristone (RU486), an antagonist of the glucocorticoid receptor. Dose response to dexamethasone (DEX) on IPP was studied at PND10 and PND20. Bacterial translocation (BT) was assessed in mesenteric lymph nodes (MLN), liver and spleen in the presence or absence of ML7. The hepatic transcriptome was studied using Agilent microarrays and qPCR on PND10 rats pretreated or not with ML7. At PND10, control pups showed basal BT to MLN while liver and spleen were sterile. A short-term MS procedure increased IPP and plasma corticosterone levels, resulted in BT to the liver and spleen and had a clear impact on the hepatic transcriptome. Most notably, several genes involved in cell division were downregulated by MS. In PND10 rats, MS-induced increase of IPP and BT were blocked by ML7 or RU486, thus demonstrating a role of the MLCK pathway and of increased plasma levels of corticosterone in these effects of MS. All these effects of MS were absent in PND20 rats. Consistently, PND20 rats were found less sensitive to DEX exposure than PND10 rats. These results show that the early life period is a critical window for a short-term mother-infant separation, which can alter the development of the gut-liver axis and facilitate bacterial passage to systemic organs.

Project description:Males and females exhibit differences in the incidence of many major diseases including auto-immune diseases, hepatocellular carcinoma, diabetes, and osteoporosis, which all have important inflammatory components in their etiology. Glucocorticoids are the primary physiological anti-inflammatory hormone in all mammals and synthetic derivatives of these hormones are widely prescribed as anti-inflammatory agents irrespective of gender. Surprisingly we report a marked sexually dimorphic regulation of gene expression by glucocorticoids in the rat liver. Eight distinct patterns of glucocorticoid regulated genes were identified and two revealed genes that respond to glucocorticoid treatment in both sexes in opposite directions (anti-correlated genes. We also identified gender-specific groups of genes regulated by glucocorticoids. Pathways analysis identified sex-specific glucocorticoid regulated gene expression in several canonical pathways that have been implicated in human disease in which disease susceptibility is sex-biased. For example, comparison of number of genes involved in inflammatory disorders between sexes, revealed 84 additional glucocorticoid responsive genes in the male rat. Our data suggests that glucocorticoids thorough sexually-dimorphic regulation of gene expression modulate gender specific homeostatic functions in male and female liver. Adult males and females adrenalectomized Sprague-Dawley rats (8-10 weeks of age) (females Distrous 1) were treated with vehicle (Phosphate Buffered Saline – 400 µl) or Dexamethasone (1mg/Kg i.p.) purchased from Steraloids (Newport, RI). Liver was harvested 6 hours after treatment and kept in RNA later solution at 4oC over night. Samples were frozen and stored at -80oC. Three replicate microarrays were completed for each group (male vehicle, male dexamethasone, female vehicle and female dexamethasone) for a total of 12 microarrays. Each microarray was hybridized using a pooled RNA sample, and each pool was created from equal amounts of total RNA from three independent RNA samples, representing individual animals (n=9 animals per group). This approach provides appropriate biological replication within the constraints of a limiting number of microarrays (C. Kendziorski, R. A. Irizarry, K. S. Chen, J. D. Haag, M. N. Gould, Proc Natl Acad Sci U S A 102, 4252 Mar 22, 2005).

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Corticosteroid-binding globulin (SERPINA6) consolidates sexual dimorphism of adult rat liver

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