title: UDCA and CDCA alleviate 17α-ethinylestradiol-induced cholestasis through PKA-AMPK pathways in rats.
abstract: Estrogen-induced cholestasis, known as intrahepatic cholestasis of pregnancy (ICP), is an estrogen-related liver disease that is widely recognized as female or pregnancy-specific. Our previous findings showed that the synthetic estrogen, 17α-ethinylestradiol (EE), induced cholestatic injury through ERK1/2-LKB1-AMP-activated protein kinase (AMPK) signaling pathway and its mediated suppression of farnesoid X receptor (FXR). To investigate the role played by bile acids in EE-induced cholestasis, we evaluated the effects of chenodeoxycholic acid (CDCA), ursodeoxycholic acid (UDCA) and deoxycholic acid (DCA) on sandwich cultured rat primary hepatocytes (SCRHs) and an in vivo rat model. Our results showed that, both CDCA and UDCA significantly induced time- and concentration-dependent reduction in AMPK phosphorylation in SCRHs. Despite having different effects on FXR activation, CDCA and UDCA both inhibited EE-induced AMPK activation, accompanied with the up-regulation of FXR and its downstream bile acid transporters. However, although DCA activates FXR and induces SHP, it was unable to alleviate EE-induced FXR suppression and further aggravated EE-induced cholestasis. We further demonstrated that both CDCA and UDCA, but not DCA, activated cyclic AMP dependent protein kinase (PKA) in SCRHs and the livers of male rats (8weeks old) liver. Furthermore, PKA antagonist, H89, blocked the AMPK inhibition by CDCA and UDCA, and pharmacological and genetic activation of PKA suppressed EE-induced AMPK activation and its downstream effects. Collectively, these results suggest that CDCA and UDCA protect against estrogen-induced cholestatic injury via PKA signaling pathway and up-regulation of EE-suppressed FXR, which suggests a potential therapeutic target for ICP.
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.
authors.forename: Xiaojiaoyang
authors.initials: X
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.
authors.forename: Zihang
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Department of Microbiology and Immunology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Runping
authors.initials: R
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China; Department of Pharmacology, Faculty of Pharmacy, University of Gezira, Wad-Medani, Sudan.
authors.forename: Hozeifa M
authors.initials: HM
authors.lastname: Hassan
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Yang
authors.affiliation: Shandong Research Academy of Traditional Chinese Medicine, Jinan, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Sun
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China; Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China. Electronic address: lyzhang@cpu.edu.cn.
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China; Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China. Electronic address: beaglejiang@cpu.edu.cn.
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Jiang
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002635:Chenodeoxycholic Acid / Q000494:pharmacology*; D002779:Cholestasis / Q000139:chemically induced / Q000517:prevention & control*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004997:Ethinyl Estradiol / Q000633:toxicity*; D005260:Female; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D010766:Phosphorylation; D011247:Pregnancy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D047428:Protein Kinase Inhibitors; C037643:bile acid binding proteins; D002635:Chenodeoxycholic Acid; D004997:Ethinyl Estradiol; D014580:Ursodeoxycholic Acid; D017868:Cyclic AMP-Dependent Protein Kinases; D000263:Adenylate Kinase
keywords: AMPK; CDCA; ICP; PKA; UDCA