Sex-dependent regulation of hepatic CYP3A by growth hormone: Roles of HNF6, C/EBPα, and RXRα

Li, Jie; Wan, Yu; Na, Shufang; Liu, Xiaochan; Dong, Guicheng; Yang, Zhongxue; Yang, Jing; Yue, Jiang

doi:10.1016/j.bcp.2014.10.010

Cited by 27 publications

(16 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CUX2 binding is seen at a subset of these female-biased HNF6 binding sites (in particular, nearby M3 genes; Figure 5 and Table 3), and is associated with female-biased gene activation. This activating effect of CUX2 on a subset of female-biased genes contrasts with the suppressive effects of CUX2 on male-biased genes (10). A subset of the sex-enriched HNF6 binding sites identified were not associated with sex-biased DHS (not illustrated).…”

Section: Discussionmentioning

confidence: 82%

Cross Talk Between GH-Regulated Transcription Factors HNF6 and CUX2 in Adult Mouse Liver

Conforto

Steinhardt

Waxman

2015

Molecular Endocrinology

View full text Add to dashboard Cite

Hepatocyte-enriched nuclear factor (HNF)6 and CUX2 are GH and STAT5-regulated homeobox transcription factors. CUX2 shows female-specific expression and contributes to liver sex differences by repressing many male-biased genes and inducing many female-biased genes, whereas HNF6 is expressed at similar levels in male and female liver. In cell-based transfection studies, CUX2 inhibited HNF6 transcriptional regulation of the sex-specific gene promoters CYP2C11 and CYP2C12, blocking HNF6 repression of CYP2C11 and HNF6 activation of CYP2C12. These inhibitory actions of CUX2 can be explained by competition for HNF6 DNA binding, as demonstrated by in vitro EMSA analysis and validated in vivo by global analysis of the HNF6 cistrome. Approximately 40 000 HNF6-binding sites were identified in mouse liver chromatin, including several thousand sites showing significant sex differences in HNF6 binding. These sex-biased HNF6-binding sites showed strong enrichment for correspondingly sex-biased DNase hypersensitive sites and for proximity to genes showing local sex-biased chromatin marks and a corresponding sex-biased expression. Further, approximately 90% of the genome-wide binding sites for CUX2 were also bound by HNF6. These HNF6/CUX2 common binding sites were enriched for genomic regions more accessible in male than in female mouse liver chromatin and showed strongest enrichment for male-biased genes, suggesting CUX2 displacement of HNF6 as a mechanism to explain the observed CUX2 repression of male-biased genes in female liver. HNF6 binding was sex independent at a majority of its binding sites, and HNF6 peaks were frequently associated with cobinding by multiple other liver transcription factors, consistent with HNF6 playing a global regulatory role in both male and female liver.

show abstract

Section: Discussionmentioning

confidence: 82%

Cross Talk Between GH-Regulated Transcription Factors HNF6 and CUX2 in Adult Mouse Liver

Conforto

Steinhardt

Waxman

2015

Molecular Endocrinology

View full text Add to dashboard Cite

show abstract

“…After DAB or fluorescence‐conjugated antibody staining, five fields of the slides were collected from each animal at 20× and 40× magnification. For immunoblot assays, the procedures were based on previous studies (Li, Wan, et al, ; Li, Xie, et al, ). Briefly, kidney extracts were resuspended in a storage solution containing 100 mM Tris (pH 7.4), 0.1 mM EDTA, 0.1 mM dithiothreitol, 1.15% (w .…”

Section: Methodsmentioning

confidence: 99%

Loganetin protects against rhabdomyolysis‐induced acute kidney injury by modulating the toll‐like receptor 4 signalling pathway

Tan

Wang

et al. 2019

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

Background and Purpose: Acute kidney injury (AKI) is a rapid renal dysfunctional disease, for which no effective drugs or therapies are available to improve prognosis.Loganetin is a natural product with unknown bioactivities. Here, we identified a new protective effect and mechanism of Loganetin in a mouse model of AKI induced by rhabdomyolysis.Experimental Approach: AKI was induced using glycerol by i.m. injection in mice models. Thirty minutes and 24 and 48 hr after injection of glycerol, the mice received 2 and 18 mg·kg −1 of Loganetin i.p. respectively. Then mice blood and kidney were collected for various biochemical and histopathological studies. Mechanistic studies on modulation of AKI by Loganetin were performed using HK-2 cells and Toll-like receptor 4 (TLR4) knockout mice.Key Results: In the Loganetin treated group, kidney damage and mortality rate were declined, and blood urea nitrogen and serum creatinine were much lower. Loganetin prevented damage to the tubular structures induced by glycerol and decreased apoptotic cells at the corticomedullary junction. In HK-2 cells, Loganetin could inhibit NF-κB pathway and pro-apoptotic genes expression. However, TLR4 was silenced by a specific shRNA, and the inhibitory effect of Loganetin in HK-2 cells vanished. Loganetin also down-regulated the expression of inflammation factors by suppressing TLR4 activity.Conclusion and Implications: All the results suggested that TLR4 plays a critical role in AKI development, and Loganetin ameliorates AKI by inhibiting TLR4 activity and blocking the JNK/p38 pathway, which provides a new strategy for AKI treatment.

show abstract

“…This parallels the higher expression and activity of CYP3A4 seen in female human liver (Wolbold et al, 2003) and is attributed to the stimulatory influence of the continuous growth hormone (GH) secretion pattern characteristic of females (Cheung et al, 2006). Several transcription factors are implicated in the female-predominant expression of CYP3A4 driven by a continuous GH profile: signal transducer and activator of transcription-5 (Lamba et al, 2016); PXR and hepatocyte nuclear factor-4a (Thangavel et al, 2011); hepatocyte nuclear factor-6, CCAAT-enhancer binding protein-a, and retinoid X receptor-a (Li et al, 2015). MC treatment suppressed hepatic CYP3A4 in female and male mice at 72 hours postdosing at the mRNA ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Suppression of HepaticCYP3A4Expression and Activity by 3-Methylcholanthrene in Humanized PXR-CAR-CYP3A4/3A7 Mice

Crosby

Riddick

2018

Drug Metab Dispos

View full text Add to dashboard Cite

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants that activate the aryl hydrocarbon receptor, thereby triggering a range of biologic responses, exemplified by the induction of CYP1A1. PAHs can also regulate the expression of members of the CYP3A subfamily, with reports of mainly suppressive effects on mouse hepatic Cyp3a11 expression, but paradoxically both inductive and suppressive effects on human hepatic CYP3A4 expression. Understanding the regulation of CYP3A4 expression by PAHs is important because of the widespread exposure of humans to these chemicals and the central role of the CYP3A4 enzyme in the metabolism of clinically important drugs and endogenous substances. The present study used 3-methylcholanthrene (MC) as a model PAH to characterize the in vivo regulation of CYP3A4 expression and activity in humanized pregnane X receptor-constitutive androstane receptor-CYP3A4/3A7 mice. Adult mice were treated by intraperitoneal injection with MC (80 mg/kg), or corn oil vehicle, and euthanized 24 or 72 hours later. As a positive control response, pronounced induction of hepatic Cyp1a1 by MC was confirmed at both time points in males and females at the mRNA, protein, and catalytic activity levels. Basal hepatic CYP3A4 expression and activity were significantly higher in female versus male mice. MC treatment suppressed hepatic CYP3A4 in female mice at 72 hours postdosing at the mRNA, protein, and catalytic activity levels. A similar response was observed in male mice, although the suppression of CYP3A4 protein levels did not achieve statistical significance. This mouse model will facilitate further studies of the mechanisms and consequences of CYP3A4 suppression by PAHs.

show abstract

Sex-dependent regulation of hepatic CYP3A by growth hormone: Roles of HNF6, C/EBPα, and RXRα

Cited by 27 publications

References 36 publications

Cross Talk Between GH-Regulated Transcription Factors HNF6 and CUX2 in Adult Mouse Liver

Cross Talk Between GH-Regulated Transcription Factors HNF6 and CUX2 in Adult Mouse Liver

Loganetin protects against rhabdomyolysis‐induced acute kidney injury by modulating the toll‐like receptor 4 signalling pathway

Suppression of HepaticCYP3A4Expression and Activity by 3-Methylcholanthrene in Humanized PXR-CAR-CYP3A4/3A7 Mice

Contact Info

Product

Resources

About