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UDCA Prevents 17α‐Ethinylestradiol‐induced Cholestatic Injury via Inhibiting AMP‐activated Protein Kinase Activation
Author(s) -
Li Xiaojiaoyang,
Liu Runping,
Yuan Zihang,
Jiang Zhenzhou,
Zhang Luyong,
Zhou Huiping
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1119.9
Subject(s) - ursodeoxycholic acid , cholestasis , cholestasis of pregnancy , ampk , bile acid , protein kinase a , amp activated protein kinase , endocrinology , medicine , farnesoid x receptor , estrogen , chemistry , downregulation and upregulation , ethinylestradiol , kinase , nuclear receptor , biology , biochemistry , fetus , transcription factor , pregnancy , population , genetics , environmental health , gene , research methodology
Cholestasis, as a common liver injury in clinic, increases the risk of other malignant hepatobiliary diseases such as hepatic carcinoma and cholangiocarcinoma. Estrogen‐induced cholestasis occurred in many susceptible women due to pregnancy or hormone therapy. Previous studies from our group and others suggest that AMP‐activated protein kinase (AMPK) induced phosphorylation of farnesoid X receptor (FXR), a key nuclear receptor involved in regulating bile acid homeostasis represents an important underlying mechanism of estrogen‐induced cholestasis. Most recent clinical study indicated that ursodeoxycholic acid (UDCA) monotherapy is effective in the treatment of intrahepatic cholestasis of pregnancy. However, the functional molecular/cellular mechanisms of UDCA‐mediated protective effect against estrogen‐induced cholestasis remains unclear and is the focus of this study. Methods The sandwich‐cultured rat primary hepatocytes and 17α‐ethinylestradiol (EE)‐induced rat cholestasis models were used. The protein levels were determined by Western blot analysis. The mRNA levels of targeted genes were determined by real‐time RT‐PCR. Immunofluorescent staining was used to detect canalicular structure of liver. Results EE significantly suppressed the expression of FXR and bile acid transporters via activation of AMPK signaling pathways. In rat primary hepatocytes, UDCA significantly inhibited EE‐induced AMPK activation and down‐regulation of FXR and bile acid transporters. UDCA rapidly and dose‐dependently induced phosphorylation of protein kinase A (PKA), which was correlated to its effect on inhibition of EE‐induced AMPK activation and down‐regulation of FXR expression. H89, a PKA inhibitor, blocked UDCA‐induced inhibitory effect on EE‐induced AMPK activation and downregulation of FXR and bile acid transporters. Furthermore, UDCA inhibited EE‐induced AMPK activation and downregulation of FXR and bile acids transporters in vivo rat cholestasis models. Conclusion UDCA protected hepatocytes from EE‐induced cholestatic injury via inhibiting AMPK activation. Our data also suggested that activation of PKA may also contribute to UDCA‐mediated protective effects. Support or Funding Information This poster presentation was supported by the Fundamental Research Funds for the Central Universities. And this study was supported by National Natural Science Foundation of China Grants (81320108029).