BackgroundIntrahepatic cholestasis of pregnancy (ICP) usually occurs in the third trimester and is associated with increased risks in fetal complications. Currently, the exact mechanism of this disease is unknown. The purpose of this study was to develop potential biomarkers for the diagnosis and prediction of ICP.MethodsWe enrolled 40 pregnant women diagnosed with ICP and 40 healthy pregnant controls. The number of placental samples and serum samples between the two groups was 10 and 40 respectively. Ultra-performance liquid chromatography tandem high-resolution mass spectrometry was used to analyze placental metabolomics. Then, we verified the differentially expressed proteins and metabolites, both placental and blood serum, in the first, second, and third trimesters.ResultsMetabolomic analysis of placental tissue revealed that fatty acid metabolism and primary bile acid biosynthesis were enriched. In the integrated proteomic and metabolomic analysis of placental tissue, peroxisomal acyl-CoA oxidase 1 (ACOX1), L-palmitoylcarnitine, and glycocholic acid were found to be three potential biomarkers. In a follow–up analysis, expression levels of both placental and serum ACOX1, L-palmitoylcarnitine, and glycocholic acid in both placenta and serum were found to be significantly higher in third-trimester ICP patients; the areas under the ROC curves were 0.823, 0.896, and 0.985, respectively. Expression levels of serum ACOX1, L-palmitoylcarnitine, and glycocholic acid were also significantly higher in first- and second-trimester ICP patients; the areas under the ROC curves were 0.726, 0.657, and 0.686 in the first trimester and 0.718, 0.727, and 0.670 in the second trimester, respectively. Together, levels of the three aforementioned biomarkers increased the value for diagnosing and predicting ICP (AUC: 0.993 for the third, 0.891 for the second, and 0.932 for the first trimesters).ConclusionsL-palmitoylcarnitine, ACOX1, and glycocholic acid levels taken together may serve as a new biomarker set for the diagnosis and prediction of ICP.
BackgroundIntrahepatic cholestasis of pregnancy (ICP) is closely related to the occurrence of adverse outcomes. Currently, total bile acids (TBAs) are the only diagnostic index for ICP, and its sensitivity and specificity have certain limitations. In this study, we aimed to develop potential biomarkers for the diagnosis of ICP.MethodsSixty pregnant women diagnosed with ICP and 48 healthy pregnant controls were enrolled in this study. We used the Agilent microRNA (miRNA) array followed by quantitative reverse transcriptase polymerase chain reaction assays to identify and validate the serum exosome miRNA profiles in ICP and healthy pregnant controls. We employed bioinformatics to identify metabolic processes associated with differentially expressed serum exosome miRNAs.ResultsThe expression levels of hsa-miR-4271, hsa-miR-1275, and hsa-miR-6891-5p in maternal serum exosomes were significantly lower in ICP patients compared to controls; the diagnostic accuracy of hsa-miR-4271, hsa-miR-1275, and hsa-miR-6891-5p was evaluated with the area under the receiver operating characteristic curve (AUC) values of 0.861, 0.886, and 0.838, respectively. Multiple logistic regression analysis showed that a combination of the levels of hsa-miR-4271and hsa-miR-1275 afforded a significantly higher AUC (0.982). The non-error rate of a combination of all three exosome miRNAs was the highest (95%), thus more reliable ICP diagnosis. The expression levels of all three exosome miRNAs were negatively associated with TBAs. Furthermore, according to bioinformatics analysis, the three exosome miRNAs were related to lipid metabolism, apoptosis, oxidative stress, and the Mitogen Activated Protein Kinase (MAPK) signaling pathway.ConclusionsThis study may identify the novel non-invasive biomarkers for ICP and provided new insights into the important role of the exosome miRNA regulation in ICP.
Background Intrahepatic cholestasis of pregnancy (ICP) is a common pregnancy specific liver disease, which has little impact on the mother and mainly causes adverse fetal outcomes. Endoplasmic reticulum protein 29 (ERp29) plays a key role in protein folding, transport and secretion, and participates in biological events such as apoptosis, oxidative stress, lipid metabolism, immune regulation and so on. Epithelial mesenchymal transformation (EMT) is the process of epithelial cells losing polarity and adhesion, and transforming into mesenchymal like phenotype through migration. Methods Subcutaneous injection of ethinyl estradiol (E2) was used to induce ICP in pregnant rats, and serum TBA, ALT and AST were detected to test whether the animal model was successfully constructed. ERp29 and EMT related molecules were detected by immunohistochemistry and western blotting. Taurocholic acid (TCA) was used to simulate the ICP environment, and TGF-β1 was added to induce the EMT process. CCK8 and TUNEL were used to detect the level of cell apoptosis. The scratch, migration, and invasion test were used to detect the EMT process of cells. ERp29 overexpression/knockdown vector were constructed and transfected to verify the role of ERp29 in the EMT process. Results The ICP animal model was successfully constructed. ERp29 in the placenta tissue of the ICP pregnant rats increased significantly, and the level of apoptosis increased. Compared with the normal, the placental tissues of the ICP group had high expression of E-cadherin and low expression of N-cadherin, snail1, vimentin. After HTR-8/Svneo cells were induced by TCA, EMT was inhibited, while the ERp29 increased. Knockdown of ERp29 reduced the inhibition of cell EMT. After the ERp29 knockdown vector was transfected into pregnant rats by adenovirus, the degree of inhibiting EMT in the placenta tissue of pregnant rats was inhibited, and the ICP progress was alleviated. Conclusion The high level of ERp29 in placental trophoblast cells inhibits the EMT process and aggravates the occurrence and development of ICP.
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