The nuclear receptor CAR modulates alcohol-induced liver injury

Chen, Xiaosong; Meng, Zhipeng; Wang, Xiaoqiong; Zeng, Samuel; Huang, Wendong

doi:10.1038/labinvest.2011.68

Cited by 21 publications

(21 citation statements)

References 24 publications

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“…Thus, TCC contamination in biological systems may be critically relevant by interfering with metabolism of endogenous and exogenous substrates by CAR-target xenobiotic genes. For example, a recent study has linked CAR pre-activation and alcohol infusion to a synergistic decrease in the expression of enzymes that metabolize the alcohol in liver including alcohol dehydrogenase 1, aldehyde dehyrogenase (ALDH) 1A1, ALDH3A2, and CYP2E1, which supports the role of CAR in modulating alcoholic liver injury [44]. Secondly, it has been characterized that PB-like agents possess CAR-dependent liver enlargement properties that are evidenced by increases in cell proliferation and suppression of apoptosis [45].…”

Section: Discussionmentioning

confidence: 93%

Triclocarban Mediates Induction of Xenobiotic Metabolism through Activation of the Constitutive Androstane Receptor and the Estrogen Receptor Alpha

Yueh

Evans

et al. 2012

PLoS ONE

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Triclocarban (3,4,4′-trichlorocarbanilide, TCC) is used as a broad-based antimicrobial agent that is commonly added to personal hygiene products. Because of its extensive use in the health care industry and resistance to degradation in sewage treatment processes, TCC has become a significant waste product that is found in numerous environmental compartments where humans and wildlife can be exposed. While TCC has been linked to a range of health and environmental effects, few studies have been conducted linking exposure to TCC and induction of xenobiotic metabolism through regulation by environmental sensors such as the nuclear xenobiotic receptors (XenoRs). To identify the ability of TCC to activate xenobiotic sensors, we monitored XenoR activities in response to TCC treatment using luciferase-based reporter assays. Among the XenoRs in the reporter screening assay, TCC promotes both constitutive androstane receptor (CAR) and estrogen receptor alpha (ERα) activities. TCC treatment to hUGT1 mice resulted in induction of the UGT1A genes in liver. This induction was dependent upon the constitutive active/androstane receptor (CAR) because no induction occurred in hUGT1Car−/− mice. Induction of the UGT1A genes by TCC corresponded with induction of Cyp2b10, another CAR target gene. TCC was demonstrated to be a phenobarbital-like activator of CAR in receptor-based assays. While it has been suggested that TCC be classified as an endocrine disruptor, it activates ERα leading to induction of Cyp1b1 in female ovaries as well as in promoter activity. Activation of ERα by TCC in receptor-based assays also promotes induction of human CYP2B6. These observations demonstrate that TCC activates nuclear xenobiotic receptors CAR and ERα both in vivo and in vitro and might have the potential to alter normal physiological homeostasis. Activation of these xenobiotic-sensing receptors amplifies gene expression profiles that might represent a mechanistic base for potential human health effects from exposure to TCC.

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Section: Discussionmentioning

confidence: 93%

Triclocarban Mediates Induction of Xenobiotic Metabolism through Activation of the Constitutive Androstane Receptor and the Estrogen Receptor Alpha

Yueh

Evans

et al. 2012

PLoS ONE

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“…Activation of other nuclear receptors, Pxr and Car, owing to elevated bile acids, LCA, and the metabolite 3-keto-5b-cholanic acid (Goodwin and Kliewer, 2002) may result in changes in transporters and enzymes. Bile acids, especially the tMCAs and elevated bilirubin levels in hFRGN livers will further contribute to varying extent of Fxr and Car induction in extrahepatic tissues (Huang et al, 2003;Chen et al, 2011). These translate to induction of targeted transporters and enzymes such as Mrp2, Mrp3, Mrp4 and Mdr1a, Gst4-4, Sult1a1, and Ugt1a1 (Huang et al, 2003;Zollner et al, 2006;Zollner and Trauner, 2009;Wagner et al, 2011) in hFRGN intestine, kidney or brain (Figs.…”

Section: Discussionmentioning

confidence: 99%

Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

Chow

Quach

Zhang

et al. 2016

J Pharmacol Exp Ther

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The humanized liver mouse model is being exploited increasingly for human drug metabolism studies. However, its model stability, intercommunication between human hepatocytes and mouse nonparenchymal cells in liver and murine intestine, and changes in extrahepatic transporter and enzyme expressions have not been investigated. We examined these issues in FRGN [fumarylacetoacetate hydrolase (Fah2/2), recombination activating gene 2 (Rag22/2), and interleukin 2 receptor subunit gamma (IL-2rg 2/2) triple knockout] on nonobese diabetic (NOD) background] and chimeric mice: mFRGN and hFRGN (repopulated with mouse or human hepatocytes, respectively). hFRGN mice showed markedly higher levels of liver cholesterol, biliary bilirubin, and bile acids (liver, bile, and plasma; mainly human forms, but also murine bile acids) but lower transforming growth factor beta receptor 2 (TGFBR2) mRNA expression levels (10%) in human hepatocytes and other proliferative markers in mouse nonparenchymal cells (Tgf-b1) and cholangiocytes [plasma membrane-bound, G protein-coupled receptor for bile acids (Tgr5)], suggestive of irregular regeneration processes in hFRGN livers. Changes in gene expression in murine intestine, kidney, and brain of hFRGN mice, in particular, induction of intestinal farnesoid X receptor (Fxr) genes: fibroblast growth factor 15 (Fgf15), mouse ileal bile acid binding protein (Ibabp), small heterodimer partner (Shp), and the organic solute transporter alpha (Osta), were observed. Proteomics revealed persistence of remnant murine proteins (cyotchrome P450 7a-hydroxylase (Cyp7a1) and other enzymes and transporters) in hFRGN livers and suggest the likelihood of mouse activity. When compared with normal human liver tissue, hFRGN livers showed lower SHP mRNA and higher CYP7A1 (300%) protein expression, consequences of tb-and ta-muricholic acid-mediated inhibition of the FXR-SHP cascade and miscommunication between intestinal Fgf15 and human liver fibroblast growth factor receptor 4 (FGFR4), as confirmed by the unchanged hepatic pERK/total ERK ratio. Dysregulation of hepatocyte proliferation and bile acid homeostasis in hFRGN livers led to hepatotoxicity, gallbladder distension, liver deformity, and other extrahepatic changes, making questionable the use of the preparation for drug metabolism studies.

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“…However, nuclear receptors are also important in ASH, CASH, and TASH. PPAR [227], PXR [228], CAR [229], LXR [230], and FXR [231] are implicated in the pathogenesis or therapy of alcoholic liver disease. Nuclear receptor activation may also be involved in the steatohepatitis associated with atypical antipsychotic medications [232].…”

Section: Nuclear Receptors In Ash Cash and Tashmentioning

confidence: 99%

Nuclear receptors and nonalcoholic fatty liver disease

Cave

Clair

Hardesty

et al. 2016

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

230

204

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Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator-activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepatocellular carcinoma. NAFLD is associated with inappropriate nuclear receptor function and perturbations along the gut:liver:adipose axis including obesity, increased intestinal permeability with systemic inflammation, abnormal hepatic lipid metabolism, and insulin resistance. Environmental chemicals may compound the problem by directly interacting with nuclear receptors leading to metabolic confusion and the inability to differentiate fed from fasting conditions. This review focuses on the impact of nuclear receptors in the pathogenesis and treatment of NAFLD. Clinical trials including PIVENS and FLINT demonstrate that nuclear receptor targeted therapies may lead to the paradoxical dissociation of steatosis, inflammation, fibrosis, insulin resistance, dyslipidemia and obesity. Novel strategies currently under development (including tissue-specific ligands and dual receptor agonists) may be required to separate the beneficial effects of nuclear receptor activation from unwanted metabolic side effects. The impact of nuclear receptor crosstalk in NAFLD is likely to be profound, but requires further elucidation. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.

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The nuclear receptor CAR modulates alcohol-induced liver injury

Cited by 21 publications

References 24 publications

Triclocarban Mediates Induction of Xenobiotic Metabolism through Activation of the Constitutive Androstane Receptor and the Estrogen Receptor Alpha

Triclocarban Mediates Induction of Xenobiotic Metabolism through Activation of the Constitutive Androstane Receptor and the Estrogen Receptor Alpha

Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

Nuclear receptors and nonalcoholic fatty liver disease

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