Activation of the farnesoid X receptor provides protection against acetaminophen-induced hepatic toxicity.
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 immunoprecipitation-based 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.
Lee
Florence Ying
FY
Department of Biological Chemistry, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90095, USA.
de Aguiar Vallim
Thomas Quad
TQ
Chong
Hansook Kim
HK
Zhang
Yanqiao
Y
Liu
Yaping
Y
Jones
Stacey A
SA
Osborne
Timothy F
TF
Edwards
Peter A
PA
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099150:Receptor, Farnesoid X-Activated
D000082:Acetaminophen; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated