Role of farnesoid X receptor in establishment of ontogeny of phase-I drug metabolizing enzyme genes in mouse liver

Peng, Lai; Piekos, Stephanie; Guo, Grace L.; Zhong, Xiao‐bo

doi:10.1016/j.apsb.2016.07.015

Cited by 14 publications

(13 citation statements)

References 35 publications

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“…FXR decreases CYP7A1 expression by several indirect mechanisms, by induction of SHP, which in turn inhibits transactivation of CYP7A1 and CYP8B1 by hepatocyte nuclear factor 4αHNF4α) and liver-related homolog-1 (LRH-1). This is in line with finding of Peng et al (2016), who reported that CYP7A1 is upregulated in young FXR nullizygous mice.…”

Section: Regulation Of Cyp Enzymes Involved In the Metabolism Of Bilesupporting

confidence: 92%

Bile Acids, Nuclear Receptors and Cytochrome P450

Juřica¹,

Dovrtělová²,

Nosková³

et al. 2016

Physiol Res

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This review summarizes the importance of bile acids (BA) as important regulators of various homeostatic mechanisms with detailed focus on cytochrome P450 (CYP) enzymes. In the first part, synthesis, metabolism and circulation of BA is summarized and BA are reviewed as physiological ligands of nuclear receptors which regulate transcription of genes involved in their metabolism, transport and excretion. Notably, PXR, FXR and VDR are the most important nuclear receptors through which BA regulate transcription of CYP genes involved in the metabolism of both BA and xenobiotics. Therapeutic use of BA and their derivatives is also briefly reviewed. The physiological role of BA interaction with nuclear receptors is basically to decrease production of toxic non-polar BA and increase their metabolic turnover towards polar BA and thus decrease their toxicity. By this, the activity of some drug-metabolizing CYPs is also influenced what could have clinically relevant consequences in cholestatic diseases or during the treatment with BA or their derivatives.

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Section: Regulation Of Cyp Enzymes Involved In the Metabolism Of Bilesupporting

confidence: 92%

Bile Acids, Nuclear Receptors and Cytochrome P450

Juřica¹,

Dovrtělová²,

Nosková³

et al. 2016

Physiol Res

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“…FXR is a member of nuclear receptor superfamily and has crucial role in controlling BA homeostasis 1. , 4.…”

Section: Discussionmentioning

confidence: 99%

Combined obeticholic acid and apoptosis inhibitor treatment alleviates liver fibrosis

Zhou

Huang

Guo

et al. 2019

Acta Pharmaceutica Sinica B

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Obeticholic acid (OCA), the first FXR-targeting drug, has been claimed effective in the therapy of liver fibrosis. However, recent clinical trials indicated that OCA might not be effective against liver fibrosis, possibly due to the lower dosage to reduce the incidence of the side-effect of pruritus. Here we propose a combinatory therapeutic strategy of OCA and apoptosis inhibitor for combating against liver fibrosis. CCl 4 -injured mice, d-galactosamine/LPS (GalN/LPS)-treated mice and cycloheximide/TNF α (CHX/TNF α )-treated HepG2 cells were employed to assess the effects of OCA, or together with IDN-6556, an apoptosis inhibitor. OCA treatment significantly inhibited hepatic stellate cell (HSC) activation/proliferation and prevented fibrosis. Elevated bile acid (BA) levels and hepatocyte apoptosis triggered the activation and proliferation of HSCs. OCA treatment reduced BA levels but could not inhibit hepatocellular apoptosis. An enhanced anti-fibrotic effect was observed when OCA was co-administrated with IDN-6556. Our study demonstrated that OCA inhibits HSCs activation/proliferation partially by regulating BA homeostasis and thereby inhibiting activation of HSCs. The findings in this study suggest that combined use of apoptosis inhibitor and OCA at lower dosage represents a novel therapeutic strategy for liver fibrosis.

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“…Genes that were expressed with an average FPKM . 1 in at least one group were considered to be significantly expressed in the liver, and this criterion was selected based on the literature (Peng et al, 2016). Differential expression of the RNA-seq data was considered at FDR-BH , 0.05.…”

Section: Regulation Of Dpgs By Car In Developing Livermentioning

confidence: 99%

RNA Sequencing Reveals Age and Species Differences of Constitutive Androstane Receptor–Targeted Drug-Processing Genes in the Liver

2017

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The constitutive androstane receptor (CAR/Nr1i3) is an important xenobiotic-sensing nuclear receptor that is highly expressed in the liver and is well known to have species differences. During development, age-specific activation of CAR may lead to modified pharmacokinetics and toxicokinetics of drugs and environmental chemicals, leading to higher risks for adverse drug reactions in newborns and children. The goal of this study was to systematically investigate the age- and species-specific regulation of various drug-processing genes (DPGs) after neonatal or adult CAR activation in the livers of wild-type, CAR-null, and humanized CAR transgenic mice. At either 5 or 60 days of age, the three genotypes of mice were administered a species-appropriate CAR ligand or vehicle once daily for 4 days (i.p.). The majority of DPGs were differentially regulated by age and/or CAR activation. Thirty-six DPGs were commonly upregulated by CAR activation regardless of age or species of CAR. Although the cumulative mRNAs of uptake transporters were not readily altered by CAR, the cumulative phase I and phase II enzymes as well as efflux transporters were all increased after CAR activation in both species. In general, mouse CAR activation produced comparable or even greater fold increases of many DPGs in newborns than in adults; conversely, humanized CAR activation produced weaker induction in newborns than in adults. Western blotting and enzyme activity assays confirmed the age and species specificities of selected CAR-targeted DPGs. In conclusion, this study systematically compared the effect of age and species of CAR proteins on the regulation of DPGs in the liver and demonstrated that the regulation of xenobiotic biotransformation by CAR is profoundly modified by age and species.

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Role of farnesoid X receptor in establishment of ontogeny of phase-I drug metabolizing enzyme genes in mouse liver

Cited by 14 publications

References 35 publications

Bile Acids, Nuclear Receptors and Cytochrome P450

Bile Acids, Nuclear Receptors and Cytochrome P450

Combined obeticholic acid and apoptosis inhibitor treatment alleviates liver fibrosis

RNA Sequencing Reveals Age and Species Differences of Constitutive Androstane Receptor–Targeted Drug-Processing Genes in the Liver

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