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

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.

Paeonia lactiflora Pall. regulates the NF-κB-NLRP3 inflammasome pathway to alleviate cholestasis in rats

“…Subsequently, IκBα is degraded from NF‐κB and ubiquitinated, which enables the activation and the translocation of NF‐κB to enter the nucleus to further activate gene transcription . Evidence shows that NF‐κB is activated during the formation process of cholestasis . In our present study, the subunit of NF‐κB is studied to determine whether PLP plays the regulation role in NF‐κB and the results showed that PLP at high (80 g/kg) and middle (40 g/kg) dose significantly reduced the mRNA and protein expression levels of p65, whereas doses of 20 g/kg had a weaker effect.…”

“…[36] Evidence shows that NF-jB is activated during the formation process of cholestasis. [37] In our present study, the subunit of NF-jB is studied to determine whether PLP plays the regulation role in NF-jB and the results showed that PLP at high (80 g/kg) and middle (40 g/kg) dose significantly reduced the mRNA and protein expression levels of p65, whereas doses of 20 g/kg had a weaker effect. To further investigate the PLP effect on NF-jB pathway, we examined the upstream activators of the NF-jB, IKK level on mRNA expression and p-IKK level of protein expression.…”

Activation of Peroxisome Proliferator-Activated Receptor γ (PPARγ) Through NF-κB/Brg1 and TGF-ß1 Pathways Attenuates Cardiac Remodeling in Pressure-Overloaded Rat Hearts

“…Our study indicated that the activation of NF-κB induced by silencing IκBα enhanced the activity of Brg1 in cardiomyocyte, as well as the expression of TGF-β 1 in cardiac fibroblasts. In addition, a growing number of studies have highlighted the interaction of PPARγ and NF-κB [37,38], in which PPARγ could inhibit NF-κB activation via several mechanisms and then repress NF-κB-mediated transcription for certain inducible gene. In our study, the activation of PPARγ by rosiglitazone significantly inhibited the expression of NF-κB in cardiac fibroblasts and cardiomyocyte, respectively.…”

Intrahepatic Cholestasis of Pregnancy

“…Women with ICP have an imbalance in the immune response to pregnancy. Zhang et al () found that ICP is associated with suppression of the Th2 immune response, resulting in increases of proinflammatory cytokine levels. Increased cytokine production is a factor in the etiology of gestational diabetes and preeclampsia (Zhang et al., ).…”

“…Zhang et al () found that ICP is associated with suppression of the Th2 immune response, resulting in increases of proinflammatory cytokine levels. Increased cytokine production is a factor in the etiology of gestational diabetes and preeclampsia (Zhang et al., ). This may explain why women with ICP are more likely to experience these comorbidities (Shemer, Marschall, Ludvigsson, & Stephansson, ).…”