Estrogen modulates transactivations of SXR-mediated liver X receptor response element and CAR-mediated phenobarbital response element in HepG2 cells

Min, Gyesik

doi:10.3858/emm.2010.42.11.074

Cited by 5 publications

(3 citation statements)

References 46 publications

(54 reference statements)

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“…Previous reports indicate that xenobiotic nuclear receptors such as hPXR share a similar pool of co-activators with the ERs, providing a platform for inhibitory “cross-talk” between nuclear receptors [97,98]. In this respect, recent studies have demonstrated that ER-mediated transcriptional activity influences other nuclear receptors [30,31,32]. In this study hepatic protein expression of CYP3A, a PXR target gene was elevated in control chow-fed hPXR mice, suggesting that PXR is activated in these mice [58].…”

Section: Discussionmentioning

confidence: 99%

“…Estrogen activity occurs via the ER, a ligand-dependent transcription factor that consists of distinct modular domains, each with unique biological functions [28,29]. Importantly, ER-mediated transcriptional activity modulates other nuclear receptors, including the peroxisome proliferator-activated receptor α (PPARα), the constitutive androstane receptor (CAR), and the pregnane X receptor [PXR; NR1I2, its human homologue, steroid and xenobiotic receptor (SXR)] [30,31,32]. While the role of nuclear receptors in obesity is now well established, information is lacking about the contribution of nuclear receptors to the gender disparity of obesity incidence in humans and the functional differences between mouse and human nuclear receptors in diet-induced obesity.…”

Section: Introductionmentioning

confidence: 99%

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Role of human pregnane X receptor in high fat diet-induced obesity in pre-menopausal female mice

Spruiell

Jones

Cullen

et al. 2014

Biochemical Pharmacology

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Obesity is a complex metabolic disorder that is more prevalent among women. Until now, the only relevant rodent models of diet-induced obesity were via the use of ovariectomized (“postmenopausal”) females. However, recent reports suggest that the xenobiotic nuclear receptor pregnane X receptor (PXR) may contribute to obesity. Therefore, we compared the roles of mouse and human PXRs in diet-induced obesity between wild type (WT) and PXR-humanized (hPXR) transgenic female mice fed either control or high-fat diets (HFD) for 16 weeks. HFD-fed hPXR mice gained weight more rapidly than controls, exhibited hyperinsulinemia, and impaired glucose tolerance. Fundamental differences were observed between control-fed hPXR and WT females: hPXR mice possessed reduced estrogen receptor α (ERα) but enhanced uncoupling protein 1 (UCP1) protein expression in white adipose tissue (WAT); increased protein expression of the hepatic cytochrome P450 3A11 (CYP3A11) and key gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose 6-phosphatase, and increased total cholesterol. Interestingly, HFD ingestion induced both UCP1 and glucokinase protein expression in WT mice, but inhibited these enzymes in hPXR females. Unlike WT mice, CYP3A11 protein, serum 17β-estradiol levels, and WAT ERα expression were unaffected by HFD in hPXR females. Together, these studies indicate that the hPXR gene promotes obesity and metabolic syndrome by dysregulating lipid and glucose homeostasis while inhibiting UCP1 expression. Furthermore, our studies indicate that the human PXR suppresses the protective role of estrogen in metabolic disorders. Finally, these data identify PXR-humanized mice as a promising in vivo research model for studying obesity and diabetes in women.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of human pregnane X receptor in high fat diet-induced obesity in pre-menopausal female mice

Spruiell

Jones

Cullen

et al. 2014

Biochemical Pharmacology

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“…Estro gens also stimulate the translocation of CAR into the nucleus, and the estrogen receptor may modulate the interaction of CAR with phenobarbital sensitive ele ments of DNA. In the nucleus, CAR interacts with DNA sites of CAR dependent genes, including MRP2 [67,74,75]. CAR is expressed to a great extent in liver cells and, as a heterodimer with RXR, activates the transcription of genes, including some cytochromes and MRPs.…”

Section: Gender Related Differences In the Expression Of Mrps And Nucmentioning

confidence: 99%

Gender-related differences in drug effects: The role of multidrug resistance proteins

Смирнова

2012

Hum Physiol

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Mechanisms of the involvement of multidrug resistance proteins (MRPs) in the formation of gen der related differences in drug effectiveness and adverse effects have been analyzed. The structure, tissue and cellular localization, substrate specificity, and functions of MRPs are discussed. The regulation of MRP expression and activity by endogenous metabolites, signaling compounds, including sex hormones, and phar maceutical agents is described. Nuclear receptors have been shown to play a role in the regulation of MRP expression. Data on gender related differences in the expression of MRPs and nuclear receptors that are involved in the induction of MRPs in the liver and kidney are presented. It is concluded that gender related differences in the expression and functional activity of MRPs in excretory organs (the liver and kidney) may significantly contribute to gender dependence of drug pharmacokinetics and effectiveness.

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Characterization of sea bass FSHβ 5′ flanking region: transcriptional control by 17β-estradiol

Muriach

Carrillo

Zanuy

et al. 2013

Fish Physiol Biochem

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The sea bass follicle-stimulating hormone 5' flanking region (sbFSHβ 5' FR) was cloned and characterized in order to study the molecular mechanisms underlying transcriptional regulation of the sbFSHβ gene. Analysis of the ~3.5 kb of this region revealed the presence of several putative cis-acting elements, including steroid hormone response elements, cAMP response elements, pituitary-specific transcription factor response elements, activator protein-1 response elements and TATA sequence. Deleted constructs containing ~3.5 kb of the sbFSHβ 5' FR fused to a luciferase reporter gene were transiently transfected into human embryonic kidney (HEK 293) and mouse mature gonadotrope (LβT2) cell lines. The sbFSHβ 5' FR was efficiently expressed under basal conditions in LβT2 but not in HEK 293, pointing to both positive and negative regulatory elements. In order to elucidate the estrogen-mediated sbFSHβ transcriptional activity, in vitro treatments with 17β-estradiol were carried out on primary cultures of pituitary cells and LβT2 cells transiently expressing luciferase under the control of sbFSHβ 5' FR. Overall, these results demonstrate that 17β-estradiol inhibits sbFSHβ gene expression directly at the level of the pituitary. However, it was also shown that estrogen did not induce changes of the sbFSH promoter-directed luciferase activity, suggesting that sbFSHβ 5'FR (~3.5 kb) activity is cell type dependent and its estrogen regulation could require cis-acting elements located upstream of the promoter region, which is characterized in this article.

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Estrogen modulates transactivations of SXR-mediated liver X receptor response element and CAR-mediated phenobarbital response element in HepG2 cells

Cited by 5 publications

References 46 publications

Role of human pregnane X receptor in high fat diet-induced obesity in pre-menopausal female mice

Role of human pregnane X receptor in high fat diet-induced obesity in pre-menopausal female mice

Gender-related differences in drug effects: The role of multidrug resistance proteins

Characterization of sea bass FSHβ 5′ flanking region: transcriptional control by 17β-estradiol

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