New Roles for Corticosteroid Binding Globulin and Opposite Expression Profiles in Lung and Liver

PLOS ONE, Dec 2019

Corticosteroid-binding globulin (CBG) is the specific plasma transport glycoprotein for glucocorticoids. Circulating CBG is mainly synthesized in liver but, its synthesis has been located also in other organs as placenta, kidney and adipose tissue with unknown role. Using an experimental model of acute pancreatitis in cbg-/- mice we investigated whether changes in CBG affect the progression of the disease as well as the metabolism of glucocorticoids in the lung. Lack of CBG does not modify the progression of inflammation associated to pancreatitis but resulted in the loss of gender differences in corticosterone serum levels. In the lung, CBG expression and protein level were detected, and it is noteworthy that these showed a sexual dimorphism opposite to the liver, i.e. with higher levels in males. Reduced expression of 11β-HSD2, the enzyme involved in the deactivation of corticosterone, was also observed. Our results indicate that, in addition to glucocorticoids transporter, CBG is involved in the gender differences observed in corticosteroids circulating levels and plays a role in the local regulation of corticosteroids availability in organs like lung.

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New Roles for Corticosteroid Binding Globulin and Opposite Expression Profiles in Lung and Liver

January New Roles for Corticosteroid Binding Globulin and Opposite Expression Profiles in Lung and Liver Jose Gulfo 0 1 2 Angelo Ledda 0 1 2 Sabrina Gea-Sorlí 0 1 2 Laia Bonjoch 0 1 2 Daniel Closa 0 1 2 Mar Grasa 0 1 2 Montserrat Esteve 0 1 2 0 1 Department of Nutrition and Food Sciences, Faculty of Biology, University of Barcelona , Barcelona , Spain , 2 CIBER Obesity and Nutrition, Institute of Health Carlos III , Madrid , Spain , 3 Department of Experimental Pathology, IIBB-CSIC-IDIBAPS , Barcelona , Spain 1 Funding: Support was provided by: Fondo Investigación Sanitaria PI09/00505 to ME MG; Fondo Investigación Sanitaria PI13/00019 to DC SG-S; Predoctoral scholarship from the University of Barcelona to JG; European and Sardinian scholarship "Master and Back" to AL; Grant from Generalitat de Catalunya (AGAUR, Grant FI DGR 2013) to LB 2 Editor: Zoltán Rakonczay, Jr., University of Szeged , HUNGARY Corticosteroid-binding globulin (CBG) is the specific plasma transport glycoprotein for glucocorticoids. Circulating CBG is mainly synthesized in liver but, its synthesis has been located also in other organs as placenta, kidney and adipose tissue with unknown role. Using an experimental model of acute pancreatitis in cbg-/- mice we investigated whether changes in CBG affect the progression of the disease as well as the metabolism of glucocorticoids in the lung. Lack of CBG does not modify the progression of inflammation associated to pancreatitis but resulted in the loss of gender differences in corticosterone serum levels. In the lung, CBG expression and protein level were detected, and it is noteworthy that these showed a sexual dimorphism opposite to the liver, i.e. with higher levels in males. Reduced expression of 11β-HSD2, the enzyme involved in the deactivation of corticosterone, was also observed. Our results indicate that, in addition to glucocorticoids transporter, CBG is involved in the gender differences observed in corticosteroids circulating levels and plays a role in the local regulation of corticosteroids availability in organs like lung. - OPEN ACCESS Data Availability Statement: All relevant data are within the paper. Competing Interests: The authors have declared that no competing interests exist. Introduction Acute pancreatitis is a serious inflammatory process with significant morbidity and mortality. The most relevant complication during acute pancreatitis is the systemic inflammation that, in the severe forms of the disease, may lead to an acute respiratory distress syndrome [ 1 ]. This pulmonary dysfunction is characterized by an influx of inflammatory leukocytes and increases in pulmonary vascular permeability, being one of the most important factors contributing to death during the first week of the disease [ 2 ]. The mechanisms responsible for the involvement of distant organs are still unclear and different pathways have been suggested, including oxygen-derived free radicals and cytokines [ 3 ]. As occurs with other critical illnesses, such as sepsis, trauma and septic shock, the hypothalamic–pituitary–adrenal axis plays an important modulatory role in the control of the inflammatory process. Several reports suggested a link between an impaired adrenal secretion and the progression of systemic inflammation in acute pancreatitis [ 4 ]. In addition, corticosteroid insufficiency has been reported in patients with acute pancreatitis [ 5 ]. Nevertheless, the use of corticosteroid in the treatment of acute pancreatitis is still being debated and experimental studies suggest that although the prophylactic use of corticosteroids showed efficacy on some features of the disease, this effect was not observed with the therapeutic use [ 6 ]. In addition to glucocorticoids, changes in the levels of corticosteroid-binding globulin (CBG) have also been reported in patients with acute pancreatitis [ 7 ][ 8 ]. CBG is the specific high-affinity plasma transport glycoprotein for glucocorticoids. It is mainly synthesized in liver, although it could be also produced by the placenta, kidney and adipose tissue [ 9 ][ 10 ][ 11 ]. The main function of CBG seems to be glucocorticoids transport since under normal conditions 80–90% of circulating cortisol is bound with high affinity to CBG, while only 10–15% binds with low affinity to albumin and the remaining 5–10% is known as “free cortisol” [ 12 ]. It is accepted that CBG actively deliver glucocorticoid to inflamed tissue due to the action of elastase released by activated neutrophils. This protease cleaves CBG and disrupts the glucocorticoid-binding site, thus resulting in the release of the corresponding glucocorticoid in the areas of inflammation [ 13 ]. However, CBG has been located also in some intracellular compartments suggesting additional, and yet unknown, functions [ 14 ]. Herein, our study was designed to investigate, in an experimental model of acute pancreatitis in mice, whether changes in CBG could affec (...truncated)


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Jose Gulfo, Angelo Ledda, Sabrina Gea-Sorlí, Laia Bonjoch, Daniel Closa, Mar Grasa, Montserrat Esteve. New Roles for Corticosteroid Binding Globulin and Opposite Expression Profiles in Lung and Liver, PLOS ONE, 2016, Volume 11, Issue 1, DOI: 10.1371/journal.pone.0146497