[Show abstract][Hide abstract] ABSTRACT: Background & aim:
Kupffer cells (KC) play a key role in the onset of inflammation in non-alcoholic steatohepatitis (NASH). The glucocorticoid receptor (GR) induces glucocorticoid-induced leucine zipper (GILZ) expression in monocytes/macrophages and is involved in several inflammatory processes. We hypothesized that the GR-GILZ axis in KC may contribute to the pathophysiology of obesity-induced liver inflammation.
By using a combination of primary cell culture, pharmacological experiments, mice deficient for the GR specifically in macrophages and transgenic mice overexpressing GILZ in macrophages, we explored the involvement of the GR-GILZ axis in KC in the pathophysiology of obesity-induced liver inflammation.
Obesity was associated with a downregulation of the GR and GILZ, and an impairment of GILZ induction by lipopolysaccharide (LPS) and dexamethasone (DEX) in KC. Inhibition of GILZ expression in isolated KC transfected with GILZ siRNA demonstrated that GILZ dowregulation was sufficient to sensitize KC to LPS. Conversely, liver inflammation was decreased in obese transgenic mice specifically overexpressing GILZ in macrophages. Pharmacological inhibition of the GR showed that impairment of GILZ induction in KC by LPS and DEX in obesity was driven by a downregulation of the GR. In mice specifically deficient for GR in macrophages, GILZ expression was low, leading to an exacerbation of obesity-induced liver inflammation.
Obesity is associated with a downregulation of the GR-GILZ axis in Kupffer cells, which promotes liver inflammation. The GR-GILZ axis in KC is an important target for the regulation of liver inflammation in obesity.
No preview · Article · Nov 2015 · Journal of Hepatology
[Show abstract][Hide abstract] ABSTRACT: The progesterone receptor (PR) with its isoforms and ligands are involved in breast tumorigenesis and prognosis. We aimed at analyzing the respective contribution of PR isoforms, PRA and PRB, in breast cancer cell proliferation in a new estrogen-independent cell based-model, allowing independent PR isoforms analysis. We used the bi-inducible human breast cancer cell system MDA-iPRAB. We studied the effects and molecular mechanisms of action of progesterone (P4) and ulipristal acetate (UPA), a new selective progesterone receptor modulator, alone or in combination. P4 significantly stimulated MDA-iPRA expressing cells proliferation. This was associated with P4-stimulated expression of the anti-apoptotic factor BCL2-L1 and enhanced recruitment of PRA, SRC-1 and RNA Pol II onto the +58 kb PR binding motif of the BCL2-L1 gene. UPA decreased cell proliferation and repressed BCL2-L1 expression in the presence of PRA, correlating with PRA and SRC1 but not RNA Pol II recruitment. These results bring new information on the mechanism of action of PR ligands in controlling breast cancer cell proliferation through PRA in an estrogen independent model. Evaluation of PR isoforms ratio, as well as molecular signature studies based on PRA target genes could be proposed to facilitate personalized breast cancer therapy. In this context, UPA could be of interest in endocrine therapy. Further confirmation in the clinical setting is required.
[Show abstract][Hide abstract] ABSTRACT: Context:
The neonatal period, notably in preterm infants, is characterized by high sodium wasting implying that aldosterone, the main hormone regulating sodium reabsorption, is unable to maintain sodium homeostasis.
Assess aldosterone secretion and action in neonates according to gestational age (GA).
Multicenter prospective study (NCT01176162) conducted between 2011-2014. Infants were followed during their first three months (M3).
Five neonatology departments in France.
The 155 newborns included were classified into three groups: <33 GW (gestational weeks) = group 1 (46 patients), 33-36 GW (67 patients) = group 2 and ≥37 GW (42 patients) = group 3.
Main outcome measures:
Plasma aldosterone was measured in umbilical cord blood. Urinary aldosterone (UAldo) was assessed at D0, D3, M1 and M3 postnatal. The correlation between UAldo and the urinary Na/K ratio was determined as an index of renal aldosterone sensitivity.
UAldo significantly increased with GA: from 8.8±7.5 μg/mmol of creatinine (group 1) to 21.1±21.0 (group 3) in correlation with plasma aldosterone levels in all groups (P<0.001), demonstrating its reliability. The aldosterone/renin ratio significantly increased with GA, suggesting an aldosterone secretion defect in preterm infants. UAldo and urinary Na/K were correlated in very preterm but not in term neonates, consistent with very preterm neonates being renal aldosterone sensitive and term neonates being aldosterone resistant.
Very preterm infants have a previously unrecognized defective aldosterone secretion but conserved renal aldosterone sensitivity in the neonatal period, which modifies the current view of sodium balance in these infants and suggests alternative management approaches.
No preview · Article · Sep 2015 · The Journal of Clinical Endocrinology and Metabolism
[Show abstract][Hide abstract] ABSTRACT: Mitotane (o,p'-DDD), the only approved drug for advanced adrenocortical carcinoma (ACC), is a lipophilic agent that accumulates into circulating lipoprotein fractions and high lipid-containing tissues.
The aim of our study was to evaluate the in vivo and in vitro biological implication of serum lipoproteins on pharmacological action of mitotane. Distribution and concentration of mitotane were studied in plasma and adrenal tissue samples from mitotane-treated patients. The impact of lipoprotein-bound or free (LP-F) mitotane was analyzed on proliferation and apoptosis of human adrenocortical H295R cells. A retrospective study of ACC patients treated or not with statins was also performed.
o,p'-DDD distribution among VLDL, LDL, HDL and lipoprotein-free (LP-F) fractions obtained after ultracentrifugation of 23 plasmas of mitotane-treated patients was widely distributed in each subfraction. A positive correlation was observed between mitotane levels in plasma and in LDL, HDL but also LP-F compartment. Intra-tumor o,p'-DDD concentrations in 5 ACC samples of mitotane-treated patients were found independent of cholesterol transporter expression, scavenger receptors (SrB1) and LDL-Receptors. In vitro studies showed significant higher anti-proliferative and pro-apoptotic effects and higher cell and mitochondrial uptake of mitotane when H295R cells were grown in LP-F medium. Finally, retrospective study of an ACC cohort of 26 mitotane-treated patients revealed that statin therapy was significantly associated with a higher rate of tumor control.
Altogether, our in vitro and in vivo studies provided compelling evidence for a greater efficacy of lipoprotein-free mitotane. ACC patients may thus benefit from therapeutic strategies that aim to increase LP-F mitotane fraction.
Full-text · Article · Jun 2015 · The Journal of Clinical Endocrinology and Metabolism
[Show abstract][Hide abstract] ABSTRACT: The salmonid corticosteroid receptors, glucocorticoid receptors 1 and 2 (GR1 and GR2) and the mineralocorticoid receptor (MR) share a high degree of homology with regard to structure, ligand- and DNA response element binding, and cellular co-localization. Typically, these nuclear hormone receptors homodimerize to confer transcriptional activation of target genes, but a few studies using mammalian receptors suggest some degree of heterodimerization. Our initial observation that the trout MR confers a several fold lower transcriptional activity compared to the trout GRs made us question the functional relevance of the MR when this receptor is located in the same cells as the GRs and activated by cortisol. A series of co-transfection experiments using different glucocorticoid response element containing promoter-reporter constructs were carried out to investigate any possible interaction between the piscine corticosteroid receptors. Co-transfection of the GRs with the MR significantly reduced the total transcriptional activity even at low MR levels, suggesting interaction between these receptors. Co-transfection of GR1 or GR2 with the MR did not affect the subcellular localization of the GRs, and the MR-mediated inhibition seemed to be independent of specific activation or inhibition of the MR. Site-directed mutagenesis of the DNA-binding domain and dimerization interface of the MR showed that the inhibition was dependent on DNA binding but not necessarily on dimerization ability. Thus, we suggest that interaction between MR and the GRs may regulate the cortisol response in cell types where the receptors co-localize and propose a dominant-negative role for the MR in cortisol mediated transcriptional activity.
Full-text · Article · Jun 2015 · Journal of Molecular Endocrinology