TY - JOUR
T1 - Activation of the farnesoid X receptor provides protection against acetaminophen-induced hepatic toxicity
AU - Lee, Florence Ying
AU - Vallim, Thomas Quad De Aguiar
AU - Chong, Hansook Kim
AU - Zhang, Yanqiao
AU - Liu, Yaping
AU - Jones, Stacey A.
AU - Osborne, Timothy F.
AU - Edwards, Peter A.
PY - 2010/8
Y1 - 2010/8
N2 - 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.
AB - 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.
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U2 - 10.1210/me.2010-0117
DO - 10.1210/me.2010-0117
M3 - Article
C2 - 20573685
AN - SCOPUS:77954995129
SN - 0888-8809
VL - 24
SP - 1626
EP - 1636
JO - Molecular Endocrinology
JF - Molecular Endocrinology
IS - 8
ER -