Optimization of stress response through the nuclear receptor-mediated cortisol signalling network

Kolodkin, Alexey; Sahin, Nilgun; Phillips, Anna; Hood, Steve R.; Bruggeman, Frank J.; Westerhoff, Hans V.; Plant, Nick

doi:10.1038/ncomms2799

Cited by 21 publications

(28 citation statements)

References 37 publications

(46 reference statements)

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“…In peripheral organs, the expression of Cyp enzymes is directly controlled by upstream xenobiotic (nr1i) and glucocorticoid (GR) nuclear receptors . The latter are activated by endogenous ligands, for example, cortisol in humans and corticosterone in mice . Interestingly, clinical evidence indicates a postictal cortisol increase in the blood of epileptic patients .…”

Section: Resultsmentioning

confidence: 99%

Hepatic and hippocampal cytochrome P450 enzyme overexpression during spontaneous recurrent seizures

et al. 2017

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SummaryObjective: Available evidence points to a role of cytochrome P450 (Cyp) drug biotransformation enzymes in central nervous system diseases, including epilepsy.Deviations in drug pharmacokinetic profiles may impact therapeutic outcomes.Here, we ask whether spontaneous recurrent seizure (SRS) activity is sufficient to modulate the expression of major Cyp enzymes in the liver and brain. Methods: Unilateral intrahippocampal (IH) kainic acid (KA) injections were used to elicit nonconvulsive status epilepticus (SE), epileptogenesis, and SRS, as monitored by video-electroencephalography. Intraperitoneal (IP) KA injection was used to trigger generalized tonic-clonic SE. KA-injected mice and sham controls were sacrificed at 24-72 hours and 1 week post-SE (IH or IP KA), and during the chronic stage (SRS; 6 weeks post-IH KA). Liver and brain tissues were processed for histology, real-time quantitative polymerase chain reaction, Western blot, or microsomal enzymatic assay. Cyp2e1, Cyp3a13, glial fibrillary acidic protein (GFAP), IBA1, xenobiotic nuclear receptors nr1i2 (PXR), nr1i3 (CAR) and nr3c1 (glucocorticoid receptor [GR]) expression was examined. Serum samples were obtained to assay corticosterone levels, a GR activator. Results: A significant increase of Cyp3a13 and Cyp2e1 transcript level and protein expression was found in the liver and hippocampi during SRS, as compared to control mice. In the ipsilateral hippocampus, Cyp2e1 and Cyp3a protein upregulation during SRS positively correlated to GFAP expression. GFAP + , and not IBA1 + , cells colocalized with Cyp2e1 or Cyp3a expression. In the liver, a trend increase in Cyp3a microsomal activity was found during SRS as compared to control mice. The transcript levels of the Cyp upstream regulators GR, xenobiotic nr1i2, and nr1i3 receptors were unchanged at SRS. Corticosterone levels, a GR ligand, were increased in the blood post-SE. Significance: SRS modifies Cyp expression in the liver and the hippocampus.Nuclear receptors or inflammatory pathways are candidate mechanisms of Cyp regulation during seizures.L. Runtz and B. Girard contributed equally to this work.

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Section: Resultsmentioning

confidence: 99%

Hepatic and hippocampal cytochrome P450 enzyme overexpression during spontaneous recurrent seizures

et al. 2017

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“…Mathematical models incorporating feedback and feedforward regulation of gene expression by high-and lowaffinity nuclear cortisol receptors support the idea that these effects improve network robustness in the face of moderate-frequency stressors (Kolodkin et al, 2013). In A. burtoni, previous work has established that the mRNA levels of several receptors, including the main steroid receptors, are regulated by social status in distinct brain regions as well as in the pituitary and testes (reviewed in Maruska and Fernald, 2014).…”

Section: Discussion Androgen Glucocorticoid and Mineralocorticoid Rementioning

confidence: 74%

Social regulation of cortisol receptor gene expression

Korzan

Grone

Fernald

2014

Journal of Experimental Biology

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In many social species, individuals influence the reproductive capacity of conspecifics. In a well-studied African cichlid fish species, Astatotilapia burtoni, males are either dominant (D) and reproductively competent or non-dominant (ND) and reproductively suppressed as evidenced by reduced gonadotropin releasing hormone (GnRH1) release, regressed gonads, lower levels of androgens and elevated levels of cortisol. Here, we asked whether androgen and cortisol levels might regulate this reproductive suppression. Astatotilapia burtoni has four glucocorticoid receptors (GR1a, GR1b, GR2 and MR), encoded by three genes, and two androgen receptors (ARα and ARβ), encoded by two genes. We previously showed that ARα and ARβ are expressed in GnRH1 neurons in the preoptic area (POA), which regulates reproduction, and that the mRNA levels of these receptors are regulated by social status. Here, we show that GR1, GR2 and MR mRNAs are also expressed in GnRH1 neurons in the POA, revealing potential mechanisms for both androgens and cortisol to influence reproductive capacity. We measured AR, MR and GR mRNA expression levels in a microdissected region of the POA containing GnRH1 neurons, comparing D and ND males. Using quantitative PCR (qPCR), we found D males had higher mRNA levels of ARα, MR, total GR1a and GR2 in the POA compared with ND males. In contrast, ND males had significantly higher levels of GR1b mRNA, a receptor subtype with a reduced transcriptional response to cortisol. Through this novel regulation of receptor type, neurons in the POA of an ND male will be less affected by the higher levels of cortisol typical of low status, suggesting GR receptor type change as a potential adaptive mechanism to mediate high cortisol levels during social suppression. KEY WORDS: Cichlid, Glucocorticoid receptors, Social stress, Androgen receptors INTRODUCTIONSocial status hierarchies are a ubiquitous organizing principle of social systems in many animal species from ants (Wilson, 2000) to primates (Cheney and Seyfarth, 1990), including humans (Chiao et al., 2009). Such hierarchies typically regulate access to resources including territories, food and/or mates, granting individuals of high status access to these resources and requiring those of low status to find alternative solutions to survive. In many species, the reproductive capacity of low status individuals is reduced and mating is not possible because of behavioral and physiological changes (e.g. Willisch et al., 2012). Typically, aggressive encounters establish and maintain social rank, which, in turn, produces significant differences in reproductive capacity. In such social systems, levels of stress and reproductive hormones directly reflect the social rank of individuals and may play a causal role in behavioral and physiological changes. RESEARCH ARTICLEThe relationship between social dominance and reproductive physiology has been well studied in an African cichlid fish, Astatotilapia burtoni (Günther 1894), in which status regulates both reproductive access and...

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“…Huh7 cells are a hepatoma cell line commonly used for in vitro assessment of toxicity and its etiology (Al-Salman and Elphick et al, 2012;Kolodkin et al, 2013Kolodkin et al, , 2010Lin et al, 2012). RD cells were derived from a human rhabdomyosarcoma and represent a mixture of spindle cells and larger multinucleated cells; these cells can also be induced to differentiate into myotubelike structures by exposure to low serum levels (Knudsen et al, 1998;Rossi et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of prenyltransferase activity by statins in both liver and muscle cell lines is not causative of cytotoxicity

et al. 2015

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Optimization of stress response through the nuclear receptor-mediated cortisol signalling network

Cited by 21 publications

References 37 publications

Hepatic and hippocampal cytochrome P450 enzyme overexpression during spontaneous recurrent seizures

Hepatic and hippocampal cytochrome P450 enzyme overexpression during spontaneous recurrent seizures

Social regulation of cortisol receptor gene expression

Inhibition of prenyltransferase activity by statins in both liver and muscle cell lines is not causative of cytotoxicity

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