Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, No 9 Jinsui Road, Tianhe District, Guangzhou, Guangdong Province, 510623, China.
Department of Pediatric Orthopedics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, 510623, China.
BMC Pregnancy Childbirth. 2024 Aug 10;24(1):525. doi: 10.1186/s12884-024-06730-6.
The pregnant women with intrahepatic cholestasis were at high risk of fetal distress, preterm birth and unexpected stillbirth. Intrahepatic cholestasis of pregnancy (ICP) was mainly caused by disorder of bile acid metabolism, whereas the specific mechanism was obscure.
We performed proteomics analysis of 10 ICP specimens and 10 placenta specimens from patients without ICP through data-independent acquisition (DIA) technique to disclose differentially expressed proteins. We executed metabolomic analysis of 30 ICP specimens and 30 placenta specimens from patients without ICP through UPLC-MS/MS to identify differentially expressed metabolites. Enrichment and correlation analysis was used to obtain the direct molecular insights of ICP development. The ICP rat models were constructed to validate pathological features.
The heatmap of proteomics analysis showed the top 30 up-regulated and 30 down-regulated proteins. The metabolomic analysis revealed 20 richer and 4 less abundant metabolites in ICP samples compared with placenta specimens from patients without ICP, and enrichment pathways by these metabolites included primary bile acid biosynthesis, cholesterol metabolism, bile secretion, nicotinate and nicotinamide metabolism, purine metabolism and metabolic pathways. Combined analysis of multiple omics results demonstrated that bile acids such as Glycohyocholic acid, Glycine deoxycholic acid, beta-Muricholic acid, Noncholic acid, cholic acid, Gamma-Mercholic Acid, alpha-Muricholic acid and Glycochenodeoxycholic Aicd were significantly associated with the expression of GLRX3, MYL1, MYH7, PGGT1B, ACTG1, SP3, LACTB2, C2CD5, APBB2, IPO9, MYH2, PPP3CC, PIN1, BLOC1S1, DNAJC7, RASAL2 and ATCN3 etc. The core protein ACAT2 was involved in lipid metabolic process and animal model showed that ACAT2 was up-regulated in placenta and liver of pregnant rats and fetal rats. The neonates had low birth weight and Safranin O-Fast green FCF staining of animal models showed that poor osteogenic and chondrogenic differentiation of fetal rats.
Multiple metabolites-alpha-Muricholic acid, beta-Muricholic acid, Glycine deoxycholic acid and Glycochenodeoxycholic Acid etc. were perfect biomarkers to predict occurrence of ICP. Bile acids were significantly associated with varieties of protein expression and these proteins were differentially expressed in ICP samples. Our study provided several biomarkers for ICP detection and potential therapeutic targets for ICP development.
患有妊娠肝内胆汁淤积症的孕妇胎儿窘迫、早产和意外死胎的风险较高。妊娠肝内胆汁淤积症（ICP）主要由胆汁酸代谢紊乱引起，但其具体机制尚不清楚。
我们通过 DIA 技术对 10 例 ICP 标本和 10 例无 ICP 患者的胎盘标本进行蛋白质组学分析，以揭示差异表达蛋白。我们通过 UPLC-MS/MS 对 30 例 ICP 标本和 30 例无 ICP 患者的胎盘标本进行代谢组学分析，以鉴定差异表达的代谢物。通过富集和相关性分析，获得 ICP 发展的直接分子见解。构建 ICP 大鼠模型验证病理特征。
蛋白质组学分析的热图显示了前 30 个上调和 30 个下调蛋白。代谢组学分析显示，与无 ICP 患者的胎盘标本相比，ICP 标本中有 20 种代谢物更丰富，4 种代谢物较少，这些代谢物的富集途径包括初级胆汁酸生物合成、胆固醇代谢、胆汁分泌、烟酸和烟酰胺代谢、嘌呤代谢和代谢途径。多组学结果的综合分析表明，甘氨胆酸、甘脱氧胆酸、β-鼠胆酸、非胆酸、胆酸、γ-羟胆酸、α-鼠胆酸和甘氨鹅脱氧胆酸等胆汁酸与 GLRX3、MYL1、MYH7、PGGT1B、ACTG1、SP3、LACTB2、C2CD5、APBB2、IPO9、MYH2、PPP3CC、PIN1、BLOC1S1、DNAJC7、RASAL2 和 ATCN3 等蛋白的表达显著相关。核心蛋白 ACAT2 参与脂质代谢过程，动物模型显示，妊娠大鼠和胎鼠的胎盘和肝脏中 ACAT2 上调。新生儿体重低，动物模型的番红 O-快绿 FCF 染色显示胎鼠成骨和软骨分化不良。
多种代谢物-α-鼠胆酸、β-鼠胆酸、甘脱氧胆酸和甘氨鹅脱氧胆酸等是预测 ICP 发生的完美生物标志物。胆汁酸与多种蛋白表达显著相关，这些蛋白在 ICP 标本中差异表达。我们的研究为 ICP 检测提供了一些生物标志物，并为 ICP 发展提供了潜在的治疗靶点。
