Activation of the farnesoid X receptor provides protection against acetaminophen-induced hepatic toxicity

Florence Ying Lee, Thomas Quad De Aguiar Vallim, Hansook Kim Chong, Yanqiao Zhang, Yaping Liu, Stacey A. Jones, Timothy Osborne, Peter A. Edwards

Research output: Contribution to journalArticle

Abstract

The nuclear receptor, farnesoid X receptor (FXR, NR1H4), is known to regulate cholesterol, bile acid, lipoprotein, and glucose metabolism. In the current study, we provide evidence to support a role for FXR in hepatoprotection from acetaminophen (APAP)-induced toxicity. Pharmacological activation of FXR induces the expression of several genes involved in phase II and phase III xenobiotic metabolism in wild-type, but not Fxr-/- mice. We used chromatin immunoprecipitationbased genome-wide response element analyses coupled with luciferase reporter assays to identify functional FXR response elements within promoters, introns, or intragenic regions of these genes. Consistent with the observed transcriptional changes, FXR gene dosage is positively correlated with the degree of protection from APAP-induced hepatotoxicity in vivo. Further, we demonstrate that pretreatment of wild-type mice with an FXR-specific agonist provides significant protection from APAP-induced hepatotoxicity. Based on these findings, we propose that FXR plays a role in hepatic xenobiotic metabolism and, when activated, provides hepatoprotection against toxins such as APAP.

Original languageEnglish (US)
Pages (from-to)1626-1636
Number of pages11
JournalMolecular Endocrinology
Volume24
Issue number8
DOIs
StatePublished - Aug 1 2010
Externally publishedYes

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Acetaminophen
Liver
Response Elements
Xenobiotics
Gene Dosage
Cytoplasmic and Nuclear Receptors
Luciferases
Bile Acids and Salts
Introns
Lipoproteins
Chromatin
Cholesterol
Genome
Pharmacology
Gene Expression
Glucose
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Lee, F. Y., Vallim, T. Q. D. A., Chong, H. K., Zhang, Y., Liu, Y., Jones, S. A., ... Edwards, P. A. (2010). Activation of the farnesoid X receptor provides protection against acetaminophen-induced hepatic toxicity. Molecular Endocrinology, 24(8), 1626-1636. https://doi.org/10.1210/me.2010-0117

Activation of the farnesoid X receptor provides protection against acetaminophen-induced hepatic toxicity. / Lee, Florence Ying; Vallim, Thomas Quad De Aguiar; Chong, Hansook Kim; Zhang, Yanqiao; Liu, Yaping; Jones, Stacey A.; Osborne, Timothy; Edwards, Peter A.

In: Molecular Endocrinology, Vol. 24, No. 8, 01.08.2010, p. 1626-1636.

Research output: Contribution to journalArticle

Lee, FY, Vallim, TQDA, Chong, HK, Zhang, Y, Liu, Y, Jones, SA, Osborne, T & Edwards, PA 2010, 'Activation of the farnesoid X receptor provides protection against acetaminophen-induced hepatic toxicity', Molecular Endocrinology, vol. 24, no. 8, pp. 1626-1636. https://doi.org/10.1210/me.2010-0117
Lee, Florence Ying ; Vallim, Thomas Quad De Aguiar ; Chong, Hansook Kim ; Zhang, Yanqiao ; Liu, Yaping ; Jones, Stacey A. ; Osborne, Timothy ; Edwards, Peter A. / Activation of the farnesoid X receptor provides protection against acetaminophen-induced hepatic toxicity. In: Molecular Endocrinology. 2010 ; Vol. 24, No. 8. pp. 1626-1636.
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