Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Molecular Medicine Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1791-2997 Online ISSN: 1791-3004
Journal Cover
June-2017 Volume 15 Issue 6

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
June-2017 Volume 15 Issue 6

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article Open Access

Constitutive androstane receptor activation promotes bilirubin clearance in a murine model of alcoholic liver disease

  • Authors:
    • Xiuyan Wang
    • Liyu Zheng
    • Jinming Wu
    • Binbin Tang
    • Mengqin Zhang
    • Debin Zhu
    • Xianfan Lin
  • View Affiliations / Copyright

    Affiliations: Department of Gastroenterology, Wenzhou People's Hospital, Wenzhou, Zhejiang 325000, P.R. China, Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
    Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 3459-3466
    |
    Published online on: April 4, 2017
       https://doi.org/10.3892/mmr.2017.6435
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Increased plasma levels of bilirubin have been reported in rat models and patients with alcoholic liver disease (ALD). The constitutive androstane receptor (CAR) is a known xenobiotic receptor, which induces the detoxification and transport of bilirubin. In the present study, the bilirubin transport regulatory mechanisms, and the role of CAR activation in hepatic and extrahepatic bilirubin clearance were investigated in a murine model of ALD. The mice were fed a Lieber-DeCarli ethanol diet or an isocaloric control diet for 4 weeks, followed by the administration of CAR agonists, 1,4-bis-[2‑(3,5-dichlorpyridyloxy)]benzene (TCPOBOP) and phenobarbital (PB), and their vehicles to examine the effect of the pharmacological activation of CAR on serum levels of bilirubin and on the bilirubin clearance pathway in ALD by serological survey, western blotting and reverse transcription‑quantitative polymerase chain reaction. The results showed that chronic ethanol ingestion impaired the nuclear translocation of CAR, which was accompanied by elevated serum levels of bilirubin, suppression of the expression of hepatic and renal organic anion transporting polypeptide (OATP) 1A1 and hepatic multidrug resistance‑associated protein 2 (MRP2), and induction of the expression of UDP-glucuronosyltransferase (UGT) 1A1. The activation of CAR by TCPOBOP and PB resulted in downregulation of the serum levels of bilirubin followed by selective upregulation of the expression levels of OATP1A1, OATP1A4, UGT1A1 and MRP2 in ALD. These results revealed the bilirubin transport regulatory mechanisms and highlighted the importance of CAR in modulating the bilirubin clearance pathway in the ALD mouse model.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

View References

1 

Orman ES, Odena G and Bataller R: Alcoholic liver disease: Pathogenesis, management, and novel targets for therapy. J Gastroenterol Hepatol. 28 Suppl 1:S77–S84. 2013. View Article : Google Scholar

2 

Chalmers DM, Rinsler MG, MacDermott S, Spicer CC and Levi AJ: Biochemical and haematological indicators of excessive alcohol consumption. Gut. 22:992–996. 1981. View Article : Google Scholar : PubMed/NCBI

3 

Torkadi PP, Apte IC and Bhute AK: Biochemical evaluation of patients of alcoholic liver disease and non-alcoholic liver disease. Indian J Clin Biochem. 29:79–83. 2014. View Article : Google Scholar : PubMed/NCBI

4 

Zollner G, Fickert P, Zenz R, Fuchsbichler A, Stumptner C, Kenner L, Ferenci P, Stauber RE, Krejs GJ, Denk H, et al: Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases. Hepatology. 33:633–646. 2001. View Article : Google Scholar : PubMed/NCBI

5 

Kardon T, Coffey MJ, Bánhegyi G, Conley AA, Burchell B, Mandl J and Braun L: Transcriptional induction of bilirubin UDP-glucuronosyltransrase by ethanol in rat liver. Alcohol. 21:251–257. 2000. View Article : Google Scholar : PubMed/NCBI

6 

Flitman R and Worth MH Jr: Inhibition of hepatic alcohol dehydrogenase by bilirubin. J Biol Chem. 241:669–672. 1966.PubMed/NCBI

7 

Bodeman CE, Dzierlenga AL, Tally CM, Mulligan RM, Lake AD, Cherrington NJ and McKarns SC: Differential regulation of hepatic organic cation transporter 1, organic anion-transporting polypeptide 1a4, bile-salt export pump and multidrug resistance-associated protein 2 transporter expression in lymphocyte-deficient mice associates with interleukin-6 production. J Pharmacol Exp Ther. 347:136–144. 2013. View Article : Google Scholar : PubMed/NCBI

8 

Keppler D: The roles of MRP2, MRP3, OATP1B1, and OATP1B3 in conjugated hyperbilirubinemia. Drug Metab Dispos. 42:561–565. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Erlinger S, Arias IM and Dhumeaux D: Inherited disorders of bilirubin transport and conjugation: New insights into molecular mechanisms and consequences. Gastroenterology. 146:1625–1638. 2014. View Article : Google Scholar : PubMed/NCBI

10 

Iusuf D, van de Steeg E and Schinkel AH: Functions of OATP1A and 1B transporters in vivo: Insights from mouse models. Trends Pharmacol Sci. 33:100–108. 2012. View Article : Google Scholar : PubMed/NCBI

11 

Wagner M, Halilbasic E, Marschall HU, Zollner G, Fickert P, Langner C, Zatloukal K, Denk H and Trauner M: CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice. Hepatology. 42:420–430. 2005. View Article : Google Scholar : PubMed/NCBI

12 

Yang H, Plösch T, Lisman T, Gouw AS, Porte RJ, Verkade HJ and Hulscher JB: Inflammation mediated down-regulation of hepatobiliary transporters contributes to intrahepatic cholestasis and liver damage in murine biliary atresia. Pediatr Res. 66:380–385. 2009. View Article : Google Scholar : PubMed/NCBI

13 

Yang H and Wang H: Signaling control of the constitutive androstane receptor (CAR). Protein Cell. 5:113–123. 2014. View Article : Google Scholar : PubMed/NCBI

14 

Tojima H, Kakizaki S, Yamazaki Y, Takizawa D, Horiguchi N, Sato K and Mori M: Ligand dependent hepatic gene expression profiles of nuclear receptors CAR and PXR. Toxicol Lett. 212:288–297. 2012. View Article : Google Scholar : PubMed/NCBI

15 

Luisier R, Lempiäinen H, Scherbichler N, Braeuning A, Geissler M, Dubost V, Müller A, Scheer N, Chibout SD, Hara H, et al: Phenobarbital Induces cell cycle transcriptional responses in mouse liver humanized for constitutive androstane and pregnane X receptors. Toxicol Sci. 139:501–511. 2014. View Article : Google Scholar : PubMed/NCBI

16 

Assenat E, Gerbal-Chaloin S, Larrey D, Saric J, Fabre JM, Maurel P, Vilarem MJ and Pascussi JM: Interleukin 1beta inhibits CAR-induced expression of hepatic genes involved in drug and bilirubin clearance. Hepatology. 40:951–960. 2004. View Article : Google Scholar : PubMed/NCBI

17 

Petrick JS and Klaassen CD: Importance of hepatic induction of constitutive androstane receptor and other transcription factors that regulate xenobiotic metabolism and transport. Drug Metab Dispos. 35:1806–1815. 2007. View Article : Google Scholar : PubMed/NCBI

18 

Saini SP, Mu Y, Gong H, Toma D, Uppal H, Ren S, Li S, Poloyac SM and Xie W: Dual role of orphan nuclear receptor pregnane X receptor in bilirubin detoxification in mice. Hepatology. 41:497–505. 2005. View Article : Google Scholar : PubMed/NCBI

19 

Chen X, Meng Z, Wang X, Zeng S and Huang W: The nuclear receptor CAR modulates alcohol-induced liver injury. Lab Invest. 91:1136–1145. 2011. View Article : Google Scholar : PubMed/NCBI

20 

Wu W, Zhu B, Peng X, Zhou M, Jia D and Gu J: Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease. Biochem Biophys Res Commun. 443:68–73. 2014. View Article : Google Scholar : PubMed/NCBI

21 

Fisher CD, Lickteig AJ, Augustine LM, Elferink RP Oude, Besselsen DG, Erickson RP and Cherrington NJ: Experimental non-alcoholic fatty liver disease results in decreased hepatic uptake transporter expression and function in rats. Eur J Pharmacol. 613:119–127. 2009. View Article : Google Scholar : PubMed/NCBI

22 

Zinchuk V, Zinchuk O, Akimaru K, Moriya F and Okada T: Ethanol consumption alters expression and colocalization of bile salt export pump and multidrug resistance protein 2 in the rat. Histochem Cell Biol. 127:503–512. 2007. View Article : Google Scholar : PubMed/NCBI

23 

Lee J, Azzaroli F, Wang L, Soroka CJ, Gigliozzi A, Setchell KD, Kramer W and Boyer JL: Adaptive regulation of bile salt transporters in kidney and liver in obstructive cholestasis in the rat. Gastroenterology. 121:1473–1484. 2001. View Article : Google Scholar : PubMed/NCBI

24 

Masereeuw R and Russel FG: Regulatory pathways for ATP-binding cassette transport proteins in kidney proximal tubules. AAPS J. 14:883–894. 2012. View Article : Google Scholar : PubMed/NCBI

25 

Geier A, Wagner M, Dietrich CG and Trauner M: Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration. Biochim Biophys Acta. 1773:283–308. 2007. View Article : Google Scholar : PubMed/NCBI

26 

van de Steeg E, Wagenaar E, van der Kruijssen CM, Burggraaff JE, de Waart DR, Elferink RP, Kenworthy KE and Schinkel AH: Organic anion transporting polypeptide 1a/1b-knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs. J Clin Invest. 120:2942–2952. 2010. View Article : Google Scholar : PubMed/NCBI

27 

Sugatani J, Kojima H, Ueda A, Kakizaki S, Yoshinari K, Gong QH, Owens IS, Negishi M and Sueyoshi T: The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR. Hepatology. 33:1232–1238. 2001. View Article : Google Scholar : PubMed/NCBI

28 

Tolson AH and Wang H: Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CAR. Adv Drug Deliv Rev. 62:1238–1249. 2010. View Article : Google Scholar : PubMed/NCBI

29 

Huang W, Zhang J, Chua SS, Qatanani M, Han Y, Granata R and Moore DD: Induction of bilirubin clearance by the constitutive androstane receptor. Proc Natl Acad Sci USA. 100:pp. 4156–4161. 2003; View Article : Google Scholar : PubMed/NCBI

30 

Huang W, Zhang J, Chua SS, Qatanani M, Han Y, Granata R and Moore DD: Induction of bilirubin clearance by the constitutive androstane receptor (CAR). Proc Natl Acad Sci USA. 100:pp. 4156–4161. 2003; View Article : Google Scholar : PubMed/NCBI

31 

Venkatesan N, Davidson MB, Simsolo RB and Kern PA: Phenobarbital treatment enhances insulin-mediated glucose metabolism and improves lipid metabolism in the diabetic rat. Metabolism. 43:348–356. 1994. View Article : Google Scholar : PubMed/NCBI

32 

Gao J, He J, Zhai Y, Wada T and Xie W: The constitutive androstane receptor is an anti-obesity nuclear receptor that improves insulin sensitivity. J Biol Chem. 284:25984–25992. 2009. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Wang X, Zheng L, Wu J, Tang B, Zhang M, Zhu D and Lin X: Constitutive androstane receptor activation promotes bilirubin clearance in a murine model of alcoholic liver disease. Mol Med Rep 15: 3459-3466, 2017.
APA
Wang, X., Zheng, L., Wu, J., Tang, B., Zhang, M., Zhu, D., & Lin, X. (2017). Constitutive androstane receptor activation promotes bilirubin clearance in a murine model of alcoholic liver disease. Molecular Medicine Reports, 15, 3459-3466. https://doi.org/10.3892/mmr.2017.6435
MLA
Wang, X., Zheng, L., Wu, J., Tang, B., Zhang, M., Zhu, D., Lin, X."Constitutive androstane receptor activation promotes bilirubin clearance in a murine model of alcoholic liver disease". Molecular Medicine Reports 15.6 (2017): 3459-3466.
Chicago
Wang, X., Zheng, L., Wu, J., Tang, B., Zhang, M., Zhu, D., Lin, X."Constitutive androstane receptor activation promotes bilirubin clearance in a murine model of alcoholic liver disease". Molecular Medicine Reports 15, no. 6 (2017): 3459-3466. https://doi.org/10.3892/mmr.2017.6435
Copy and paste a formatted citation
x
Spandidos Publications style
Wang X, Zheng L, Wu J, Tang B, Zhang M, Zhu D and Lin X: Constitutive androstane receptor activation promotes bilirubin clearance in a murine model of alcoholic liver disease. Mol Med Rep 15: 3459-3466, 2017.
APA
Wang, X., Zheng, L., Wu, J., Tang, B., Zhang, M., Zhu, D., & Lin, X. (2017). Constitutive androstane receptor activation promotes bilirubin clearance in a murine model of alcoholic liver disease. Molecular Medicine Reports, 15, 3459-3466. https://doi.org/10.3892/mmr.2017.6435
MLA
Wang, X., Zheng, L., Wu, J., Tang, B., Zhang, M., Zhu, D., Lin, X."Constitutive androstane receptor activation promotes bilirubin clearance in a murine model of alcoholic liver disease". Molecular Medicine Reports 15.6 (2017): 3459-3466.
Chicago
Wang, X., Zheng, L., Wu, J., Tang, B., Zhang, M., Zhu, D., Lin, X."Constitutive androstane receptor activation promotes bilirubin clearance in a murine model of alcoholic liver disease". Molecular Medicine Reports 15, no. 6 (2017): 3459-3466. https://doi.org/10.3892/mmr.2017.6435
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team