Dysregulated Hepatic Expression of Glucose Transporter Type-1,Toll-Like Receptor 4,and Nuclear Factor Kappa B in Estrogen-Induced Cholestasis Pregnant Rats with Placental Ischemia-Reperfusion Stress

Objective:This study aimed at investigating the expression of nuclear factor kappa B(NF-κB)and mammalian target of rapamycin(mTOR)related signal pathways in liver tissues of intrahepatic cholestasis of pregnancy animal models.Methods:Estrogen(EE)-induced cholestasis and a placental ischemia-reperfusion(IR)model were established in pregnant rats.All pregnant rats were divided into four groups by random number table:EE-IR group(n=6),EE-sham group(n=6),control-IR group(n=6)and control-sham group(n=6).Liver expression of mTOR,its upstream regulator DNA damage response-1(REDD1),and downstream factor glucose transporter type-1(GLUT1),accompanied by NF-κB(p65 is the most important component),its activator toll-like receptor 4(TLR4),and inhibitor IκBα,were detected by western blot analysis and real-time polymerase chain reaction.The intergroup comparisons were performed with a one-way analysis of variance,the comparisons among groups were analyzed with the nonparametric Kruskal-Wallis test.Results:Giving pregnant rats EE alone reduced the hepatic expression of IκBα(0.72±0.20vs.1.01±0.07,P=0.008).Meanwhile,giving pregnant rats placental IR alone increased liver levels of REDD1(3.24±0.98vs.1.06±0.24,P=0.025),GLUT1(2.37±0.82vs.1.09±0.10,P=0.039),TLR4(2.12±0.29vs.1.20±0.28,P=0.010),and p65(2.09±0.85vs.1.04±0.06,P=0.023),and decreased hepatic mTOR(0.50±0.07vs.1.01±0.03,P=0.001)and IκBα(0.61±0.08vs.1.01±0.07,P=0.014)expression.Subjecting EE-treated rats to placental IR did not further alter liver levels of GLUT1(2.02±0.45vs.1.79±0.39,P=0.240),TLR4(2.10±0.74vs.1.60±0.36,P=0.129),or p65(2.41±0.83vs.1.65±0.46,P=0.145),whereas it did decrease hepatic mTOR(0.42±0.09vs.0.90±0.14,P=0.008)and IκBα(0.43±0.09vs.0.72±0.20,P=0.004)expression and enhance REDD1 expression(4.46±0.65vs.2.05±0.47,P=0.009).Placental IR stress did impact the hepatic expression of REDD1-mTOR-GLUT1 and TLR4/NF-κB/IκBαin pregnant rats.Conclusion:Placental IR-induced hepatic GLUT1,TLR4,and p65 alternation,which responded efficiently in control rats,were impaired in EE-induced ICP rats.