Project description:Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease, which can lead to adverse fetal outcomes, including preterm labor and intrauterine death. The pathogenesis of ICP is still unclear. We hypothesized that pathological index leads to abnormal placenta changes in ICP. Investigation of these differences in protein expression in parallel profiling is essential to understand the comprehensive pathophysiological mechanism underlying intrahepatic cholestasis of pregnancy(ICP)
Project description:Intrahepatic cholestasis of pregnancy (ICP) is strongly associated withan increased risk of adverse perinatal outcomes. Total bile acid (TBA) levels in the late second or third trimester are a major factor in the diagnosis. Here, we sought to establish the miRNA expression profile of plasma exosomes of ICP and identify possible biomarkers for the diagnosis of ICP.
Project description:The occurrence of hepatic cholestasis during pregnancy is accompanied by the disorders of glucose and lipid metabolism, especially the acceleration of glycolysis. Here, we reported a novel mechanism that the glycolysis metabolic intermediate lactate-induced histone 4 at K12 (H4K12) hyperlactylation aggravates bile acid (BA) dysfunction in intrahepatic cholestasis during pregnancy by activating c-JUN and in turn facilitating RXRɑ cytoplasmic relocalization. Lactylome analysis in livers of late pregnant sows with high levels of BA revealed induction of H4K12 hyperlactylation. Target correction of aberrant histone lactylation prevented the hepatic BA disorders in both sows and mice models. Mechanistically, H4K12la was enriched in promoter regions of c-JUN and activated its expression Moreover, activated c-JUN facilitated the RXRɑ phosphorylation and cytoplasmic relocalization, which resulted in the activation of whole BA synthesis pathway and inhibition of BA transport pathway. Inhibitor of the glycolysis pathway and lactate inhibitor as nutritional intervention ameliorated BA metabolic disorder in pregnant sows and cholestasis in mice. Our findings demonstrate the catalytic role of lactate on hepatic BA disorders in late pregnancy, we also provided a novel pattern of nutritional intervention to precisely target and regulate bile acid metabolism, and may open the new direction of nutritional epigenetic regulation of metabolic diseases.
Project description:We used microarrays to provide a transcriptomic signature of different types of cholestasis evoked by 3 different drugs and obstructive surgery Adverse outcome pathways (AOPs) have been recently introduced as tools to map the mechanisms underlying toxic events relevant for chemical risk assessment. AOPs particularly depict the linkage between a molecular initiating event and an adverse outcome through a number of intermediate key events. An AOP has been previously introduced for cholestatic liver injury. The objective of this study was to test the robustness of this AOP for different types of cholestatic insult and the in vitro to in vivo extrapolation. For this purpose, in vitro samples from human hepatoma HepaRG cell cultures were exposed to cholestatic drugs (i.e. intrahepatic cholestasis), while in vivo samples were obtained from livers of cholestatic mice (i.e. extrahepatic cholestasis). The occurrence of cholestasis in vitro was confirmed through analysis of bile transporter functionality and bile acid analysis. Transcriptomic analysis revealed inflammation and oxidative stress as key events in both types of cholestatic liver injury. Major transcriptional differences between intrahepatic and extrahepatic cholestatic liver insults were observed at the level of cell death and metabolism. Novel key events identified by pathway analysis included endoplasmic reticulum stress in intrahepatic cholestasis, and autophagy and necroptosis in both intrahepatic as extrahepatic cholestasis. This study demonstrates that AOPs constitute dynamic tools that should be frequently updated with new input information.
Project description:Liver biopsy samples were obtained from 64 infants with biliary atresia at the time of intraoperative cholangiogram. Liver biopsy samples were obtained from 14 age-matched infants with other causes of intrahepatic cholestasis, and from 7 deceased-donor children. GeneChip® Human Gene 1.0 ST Array (Affymetrix, CA) were used to screen mRNAs whose expression was specifically regulated in the livers from patients with biliary atresia. Gene expression profiling: Liver biopsy samples obtained from infantas with other causes of intrahepatic cholestasis were served as diseased control. Liver tissue obtained from deceased-donor children were served as normal control. A molecular signataure of biliary atresia at the time of diagnosis was identified by comparing hepatic gene expression profile from biliary atresia to those from diseased and normal controls. This dataset is part of the TransQST collection.