Roles of PPARγ/NF-κB Signaling Pathway in the Pathogenesis of Intrahepatic Cholestasis of Pregnancy

Zhiyi Lu,Jingying Xiang,Yan Cui,Lingqing Hu,Ting Zhang,Liyi Cai,Zhigang Qi,Yan Zhang,Yongxiang Yin,Xiaoping Huang

doi:10.1371/journal.pone.0087343

Abstract

BackgroundIntrahepatic cholestasis of pregnancy (ICP) is the most prevalent pregnancy specific liver disease. However, the pathogenesis and etiology of ICP is poorly understood.AimTo assess the expression of peroxisome proliferator-activated receptorγ (PPARγ) and nuclear factor kappa B (NF-κB) in placenta and HTR-8/SVneo cell, and evaluate the serum levels of cytokines, bile acids, hepatic function and lipids in control and ICP patients and the fetal outcome, in order to explore the role of PPARγ/NF-κB signaling pathway in the possible mechanism of ICP.MethodsClinical data of the pregnant women were collected and serum levels of cytokines, bile acids, hepatic function and lipids were measured. Expressions of PPARγ and NF-κB in placenta and HTR-8/SVneo cell were determined. The new-born information was collected to demonstrate the relationship between PPARγ/NF-κB signaling pathway and ICP.ResultsThe serum levels of bile acids, hepatic function, triglycerides (TG), total cholesterol (TC), IL-6, IL-12 and TNF-α in ICP group were significantly increased (P<0.01), and serum level of IL-4 was significantly decreased (P<0.01). PPARγ and NF-κB staining were found in the membrane and cytoplasm of placental trophoblast cell. The expression of PPARγ and NF-κB were significantly higher in ICP group and taurocholate acid (TCA) treated HTR-8/SVneo cell (P<0.01). The new-born information in severe ICP group were significantly different as compared to that in control group (P<0.05), and part of information in mild ICP group were also difference to that in control group (P<0.05).ConclusionsThe higher expressions of PPARγ and NF-κB in ICP placenta and TCA treated HTR-8/SVneo cell, together with the abnormal serum levels of cytokines, might induced by the imbalance of inflammatory and immune reaction, and then disturb placental bile acid and serum lipids transportation, finally result in fatal cholestasis which probably be one of the mechanism of ICP.

Highlights

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy specific disease and has a prevalence that varies by geography and ethnicity [1,2]
Our results showed that peroxisome proliferator-activated receptorc (PPARc) and nuclear factor kappa B (NF-kB) staining were found in the membrane and cytoplasm of placental trophoblast cell and PPARc (A, B, C) and NF-kB (D, E, F) protein expressions in ICP patients were significantly higher than control patients
Our studies showed that PPARc and NF-kB protein are predominantly expressed in the membrane and cytoplasm of placental trophoblast cell, and PPARc and NF-kB mRNA and protein expression were significantly up-regulated in ICP placentas and taurocholate acid (TCA) treated HTR-8/SVneo cells

Summary

Introduction

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy specific disease and has a prevalence that varies by geography and ethnicity [1,2]. The occurrence rate of ICP varies worldwide ranging from 0.1% to 15% [6]. In China, ICP is considered to be common, with an incidence of 0.8%–12.0% [7]. The treatments to ICP only alleviate the mother’s itching, which cannot relieve the harm to the fetus [8]. Study the molecular mechanisms of pathogenesis in the ICP development process seems very important. Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent pregnancy specific liver disease. The pathogenesis and etiology of ICP is poorly understood

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