RGD Reference Report - Role of AMP-activated protein kinase α1 in 17α-ethinylestradiol-induced cholestasis in rats. - Rat Genome Database

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

Authors: Li, Xiaojiaoyang  Liu, Runping  Luo, Lan  Yu, Linxi  Chen, Xin  Sun, Lixin  Wang, Tao  Hylemon, Phillip B  Zhou, Huiping  Jiang, Zhenzhou  Zhang, Luyong 
Citation: Li X, etal., Arch Toxicol. 2017 Jan;91(1):481-494. doi: 10.1007/s00204-016-1697-8. Epub 2016 Apr 18.
RGD ID: 15090804
Pubmed: (View Article at PubMed) PMID:27090119
DOI: Full-text: DOI:10.1007/s00204-016-1697-8

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.



Disease Annotations    
cholestasis  (IEP,ISO)

Gene-Chemical Interaction Annotations    
17alpha-ethynylestradiol  (EXP,ISO)
acadesine  (EXP,ISO)
dorsomorphin  (EXP,ISO)
GW 4064  (EXP,ISO)
U0126  (EXP,ISO)

Gene Ontology Annotations    

Cellular Component
cytoplasm  (IDA)
nucleus  (IDA)

Molecular Pathway Annotations    
Objects Annotated

Genes (Rattus norvegicus)
Abcb11  (ATP binding cassette subfamily B member 11)
Abcc2  (ATP binding cassette subfamily C member 2)
Nr1h4  (nuclear receptor subfamily 1, group H, member 4)
Prkaa1  (protein kinase AMP-activated catalytic subunit alpha 1)
Slc10a1  (solute carrier family 10 member 1)
Slco1a4  (solute carrier organic anion transporter family, member 1a4)

Genes (Mus musculus)
Abcb11  (ATP-binding cassette, sub-family B (MDR/TAP), member 11)
Abcc2  (ATP-binding cassette, sub-family C (CFTR/MRP), member 2)
Nr1h4  (nuclear receptor subfamily 1, group H, member 4)
Prkaa1  (protein kinase, AMP-activated, alpha 1 catalytic subunit)
Slc10a1  (solute carrier family 10 (sodium/bile acid cotransporter family), member 1)
Slco1a4  (solute carrier organic anion transporter family, member 1a4)

Genes (Homo sapiens)
ABCB11  (ATP binding cassette subfamily B member 11)
ABCC2  (ATP binding cassette subfamily C member 2)
NR1H4  (nuclear receptor subfamily 1 group H member 4)
PRKAA1  (protein kinase AMP-activated catalytic subunit alpha 1)
SLC10A1  (solute carrier family 10 member 1)


Additional Information