Regulatory Effect of Hypoxia-inducible Factor-2α on Cardiotrophin-1 in Cholestatic Disease / 胃肠病学

ABSTRACT

Cardiotrophin-1 (CT-1) is an important regulator of organ protection and glucose and lipid metabolism. Aims: To explore the role of hypoxia-inducible factors (HIFs) in regulating CT-1 expression in cholestatic disease. Methods: Twenty-three pediatric biliary atresia patients and 7 healthy liver donors were enrolled from Jun. 2016 to Jun. 2017 at Renji Hospital, School of Medicine, Shanghai Jiao Tong University. Cellular localization and expressions of HIF-1α, HIF-2α and CT-1 in liver tissue were detected by immunohistochemistry and Western blotting. In in vitro study, human umbilical vein endothelial cells (HUVECs) were treated with H2O2, a strong oxidizer, with or without silencing the expression of HIF-2α with RNA interference, and the expressions of HIF-2α and CT-1 were determined by Western blotting and real-time PCR. Results: In pediatric cholestatic liver tissue, HIF-2α and CT-1 were co-distributed in cholangiocytes and stromal cells such as vascular endothelial cells and inflammatory cells, while HIF-1α was only expressed in some inflammatory cells occasionally. Western blotting showed elevated expressions of HIF-2α and CT-1 in pediatric cholestatic liver tissue when compared with that of healthy controls. H2O2-induced oxidative stress could significantly increase the expressions of HIF-2α and CT-1 in HUVECs, while silencing of HIF-2α could significantly decrease the transcription of CT-1 induced by H2O2. Conclusions: HIF-2α but not HIF-1α regulates the expression of CT-1 in pediatric cholestatic disease. In cholestasis, oxidative stress may induce CT-1 expression via HIF-2α-dependent pathway.