Retinoic acid represses CYP7A1 expression in human hepatocytes and HepG2 cells by FXR/RXR-dependent and independent mechanisms

Cai, Shi‐Ying; He, Hongwei; Nguyen, Thanh Thao; Mennone, Albert; Boyer, James L.

doi:10.1194/jlr.m005546

Cited by 74 publications

(74 citation statements)

References 54 publications

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“…In the present study, we demonstrate that RXRa [(1)-9-cis-retinoic acid] also induces SHP. This result is in line with the induction of SHP by all-transretinoic acid (Cai et al, 2010), and suggests that SHP can be regulated by retinoids via RXRa homodimers or RXRa-RAR heterodimers. Nevertheless, increased SHP expression by RXRa could also be mediated by other heterodimers, such as RXRa-FXR, RXRa-LXRa, or RXRa-PPARg (Kim et al, 2007).…”

Section: Discussionsupporting

confidence: 70%

Repression of the Nuclear Receptor Small Heterodimer Partner by Steatotic Drugs and in Advanced Nonalcoholic Fatty Liver Disease

et al. 2015

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The small heterodimer partner (SHP) (NR0B2) is an atypical nuclear receptor that lacks a DNA-binding domain. It interacts with and inhibits many transcription factors, affecting key metabolic processes, including bile acid, cholesterol, fatty acid, and drug metabolism. Our aim was to determine the influence of steatotic drugs and nonalcoholic fatty liver disease (NAFLD) on SHP expression and investigate the potential mechanisms. SHP was found to be repressed by steatotic drugs (valproate, doxycycline, tetracycline, and cyclosporin A) in cultured hepatic cells and the livers of different animal models of NAFLD: iatrogenic (tetracycline-treated rats), genetic (glycine N-methyltransferase-deficient mice), and nutritional (mice fed a methionine-and choline-deficient diet). Among the different transcription factors investigated, CCAATenhancer-binding protein a (C/EBPa) showed the strongest dominant-repressive effect on SHP expression in HepG2 and human hepatocytes. Reporter assays revealed that the inhibitory effect of C/EBPa and steatotic drugs colocalize between 2340 and 2509 base pair of the SHP promoter, and mutation of a predicted C/EBPa response element at 2473 base pair abolished SHP repression by both C/EBPa and drugs. Moreover, inhibition of major stress signaling pathways demonstrated that the mitogen-activated protein kinase kinase 1/2 pathway activates, while the phosphatidylinositol 3 kinase pathway represses SHP in a C/EBP-dependent manner. We conclude that SHP is downregulated by several steatotic drugs and in advanced NAFLD. These conditions can activate signals that target C/EBPa and consequently repress SHP, thus favoring the progression and severity of NAFLD.

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Section: Discussionsupporting

confidence: 70%

Repression of the Nuclear Receptor Small Heterodimer Partner by Steatotic Drugs and in Advanced Nonalcoholic Fatty Liver Disease

et al. 2015

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“…Retinoic Acid Modulates CYP2D6 Expression-A previous study reported that atRA (the bioactive form of vitamin A) induces SHP expression in HepG2 cells (36). To examine whether changes in RA levels are potentially responsible for CYP2D6 induction during pregnancy, hepatic levels of the two predominant RA isomers atRA and 13cRA were measured by using liquid chromatography-mass spectrometry.…”

Section: Cyp2d6 Induction During Pregnancy Is Abrogated Inmentioning

confidence: 99%

Altered Expression of Small Heterodimer Partner Governs Cytochrome P450 (CYP) 2D6 Induction during Pregnancy in CYP2D6-humanized Mice

Koh

Pan

Shen

et al. 2014

Journal of Biological Chemistry

117

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Background: CYP2D6-mediated drug metabolism is enhanced during pregnancy, but the underlying mechanisms remain unknown. Results: In CYP2D6-humanized mice, CYP2D6 induction during pregnancy was linked to decreased expression of SHP, a repressor of CYP2D6 expression. Conclusion: Decreased SHP expression may account for CYP2D6 induction during pregnancy. Significance: This may provide a mechanistic basis in designing optimal dosage regimens in pregnant women.

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“…Retinoids are a class of compounds chemically related to vitamin A, which are essential for development and reproduction. Alltrans retinoic acid (the bioactive form of vitamin A) was previously shown to induce SHP expression in HepG2 cells (Cai et al, 2010). In Tg-CYP2D6 mice, hepatic levels of all-trans retinoic acid exhibited an approximately 2-fold decrease at term pregnancy compared with the prepregnancy levels.…”

Section: Interindividual Variability In Cyp2d6-mediated Drugmentioning

confidence: 99%

Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism

Tracy¹,

Chaudhry²,

Prasad³

et al. 2015

Drug Metabolism and Disposition

151

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The cytochrome P450 (P450) enzymes are the predominant enzyme system involved in human drug metabolism. Alterations in the expression and/or activity of these enzymes result in changes in pharmacokinetics (and consequently the pharmacodynamics) of drugs that are metabolized by this set of enzymes. Apart from changes in activity as a result of drug-drug interactions (by P450 induction or inhibition), the P450 enzymes can exhibit substantial interindividual variation in basal expression and/or activity, leading to differences in the rates of drug elimination and response. This interindividual variation can result from a myriad of factors, including genetic variation in the promoter or coding regions, variation in transcriptional regulators, alterations in microRNA that affect P450 expression, and ontogenic changes due to exposure to xenobiotics during the developmental and early postnatal periods. Other than administering a probe drug or cocktail of drugs to obtain the phenotype or conducting a genetic analysis to determine genotype, methods to determine interindividual variation are limited. Phenotyping via a probe drug requires exposure to a xenobiotic, and genotyping is not always well correlated with phenotype, making both methodologies less than ideal. This article describes recent work evaluating the effect of some of these factors on interindividual variation in human P450-mediated metabolism and the potential utility of endogenous probe compounds to assess rates of drug metabolism among individuals.

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Retinoic acid represses CYP7A1 expression in human hepatocytes and HepG2 cells by FXR/RXR-dependent and independent mechanisms

Cited by 74 publications

References 54 publications

Repression of the Nuclear Receptor Small Heterodimer Partner by Steatotic Drugs and in Advanced Nonalcoholic Fatty Liver Disease

Repression of the Nuclear Receptor Small Heterodimer Partner by Steatotic Drugs and in Advanced Nonalcoholic Fatty Liver Disease

Altered Expression of Small Heterodimer Partner Governs Cytochrome P450 (CYP) 2D6 Induction during Pregnancy in CYP2D6-humanized Mice

Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism

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