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

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.

• Authors: Xiaojiaoyang Li, Runping Liu, Lan Luo, Linxi Yu, Xin Chen, Lixin Sun, Tao Wang, Phillip B Hylemon, Huiping Zhou, Zhenzhou Jiang, Luyong Zhang
• Journal: Archives of toxicology (Arch Toxicol) Vol. 91 Issue 1 Pg. 481-494 (Jan 2017) ISSN: 1432-0738 [Electronic] Germany
• PMID: 27090119 (Publication Type: Journal Article)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 11
• ATP-Binding Cassette Transporters
• Abcb11 protein, rat
• Bile Acids and Salts
• Estrogens
• Protein Kinase Inhibitors
• Receptors, Cytoplasmic and Nuclear
• farnesoid X-activated receptor
• Ethinyl Estradiol
• Cyclic AMP
• AMP-Activated Protein Kinases
• Prkaa1 protein, rat

Topics

• AMP-Activated Protein Kinases (antagonists & inhibitors, chemistry, genetics, metabolism)
• ATP Binding Cassette Transporter, Subfamily B, Member 11
• ATP-Binding Cassette Transporters (antagonists & inhibitors, genetics, metabolism)
• Active Transport, Cell Nucleus (drug effects)
• Animals
• Bile Acids and Salts (metabolism)
• Cells, Cultured
• Cholestasis (chemically induced, enzymology, pathology, prevention & control)
• Cyclic AMP (metabolism)
• Disease Models, Animal
• Enzyme Activation (drug effects)
• Estrogens (adverse effects, chemistry)
• Ethinyl Estradiol (adverse effects, antagonists & inhibitors)
• Hepatocytes (drug effects, metabolism, pathology)
• Male
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Protein Processing, Post-Translational (drug effects)
• RNA Interference
• Random Allocation
• Rats, Sprague-Dawley
• Receptors, Cytoplasmic and Nuclear (antagonists & inhibitors, genetics, metabolism)
• Second Messenger Systems (drug effects)