期刊
MOLECULAR ENDOCRINOLOGY
卷 24, 期 8, 页码 1626-1636出版社
OXFORD UNIV PRESS INC
DOI: 10.1210/me.2010-0117
关键词
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资金
- National Institutes of Health [HL30568, HL68445, T1507443]
- Laubisch Fund
- U.S. Public Health Service National Research Service [GM07185]
- American Heart Association [0565173Y, DK70121]
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. (Molecular Endocrinology 24: 1626-1636, 2010)
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