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Arch Toxicol. 2017 Jan;91(1):481-494. doi: 10.1007/s00204-016-1697-8. Epub 2016 Apr 18.

Role of AMP-activated protein kinase α1 in 17α-ethinylestradiol-induced cholestasis in rats.

Li X1,2, Liu R1,3, Luo L1, Yu L1, Chen X1, Sun L1, Wang T1,2, Hylemon PB3,4, Zhou H5,6, Jiang Z7,8, Zhang L9,10.

Author information

1
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, Jiangsu, China.
2
Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, Jiangsu, China.
3
Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, 23298, USA.
4
McGuire Veterans Affairs Medical Center, Richmond, VA, 23249, USA.
5
Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, 23298, USA. Huiping.Zhou@vcuhealth.org.
6
McGuire Veterans Affairs Medical Center, Richmond, VA, 23249, USA. Huiping.Zhou@vcuhealth.org.
7
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, Jiangsu, China. beaglejiang@cpu.edu.cn.
8
Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, Jiangsu, China. beaglejiang@cpu.edu.cn.
9
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, Jiangsu, China. lyzhang@cpu.edu.cn.
10
Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, Jiangsu, China. lyzhang@cpu.edu.cn.

Abstract

Estrogen-induced cholestasis occurs in many women who are susceptible due to pregnancy or hormone replacement therapy for postmenopausal syndrome. 17α-Ethinylestradiol (EE), as a synthetic estrogen, has been widely used to study the underlying mechanisms of estrogen-induced cholestasis. Recent studies have also reported that liver kinase B1 (LKB1)-mediated activation of AMP-activated protein kinase (AMPK) plays a critical role in the regulation of canalicular network formation. However, the role of AMPK in EE-induced cholestasis remains to be determined. In this study, the effects of EE (1-100 µM) on AMPK activation and the expression of farnesoid X receptor (FXR) and hepatic bile acid transporters were examined in in vitro using 3D-cultured rat primary hepatocytes and in in vivo using rat cholestasis models. We also used specific chemical agonist and antagonist of AMPK, AMPK subunit-specific antibodies and lentiviral shRNAs for AMPKα1 and AMPKα2 to delineate the role of AMPK in EE-induced cholestasis and potential cellular mechanisms. We found that EE-induced phosphorylation of AMPKα1 via extracellular signal-regulated kinases-LKB1-mediated signaling pathways and subsequent nuclear translocation accounted for the down-regulation of FXR and bile acid transporters and disruption of bile acid homeostasis. Inhibition of AMPK activation using an AMPK antagonist Compound C (2 µM) or down-regulation of AMPKα1 using gene-specific shRNA attenuated EE-induced cholestasis both in in vitro and in in vivo. In conclusion, these results revealed that activation of cAMP-ERK-LKB1-AMPKα1 signaling pathway plays a critical role in EE-mediated dysregulation of the expression of FXR and bile acid transporters. AMPKα1 may represent an important therapeutic target for estrogen-induced cholestasis.

KEYWORDS:

AMPKα1; Bile acid transporters; Cholestasis; Estrogen; FXR

PMID:
27090119
PMCID:
PMC5069111
DOI:
10.1007/s00204-016-1697-8
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no competing financial interest.

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