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目的 探讨内质网应激(ERS)抑制剂4-苯基丁酸(4-PBA)对细菌脂多糖(LPS)诱导的妊娠晚期小鼠胆汁酸代谢紊乱的改善作用，阐明ERS在妊娠期肝内胆汁淤积症(ICP)中的调控机制。方法 将24只孕鼠随机分为对照组、LPS组、4-PBA组及LPS+4-PBA组。LPS组于妊娠第16天腹腔注射LPS(200μg/kg),4-PBA组腹腔注射4-PBA(150 mg/kg),LPS+4-PBA组在腹腔注射4-PBA(150 mg/kg)后1 h再腹腔注射LPS(200μg/kg)。所有孕鼠在LPS处理后6 h检测血清总胆汁酸(TBA)、肝损伤标志物、胆汁酸谱及其关键基因和蛋白表达。结果 LPS暴露升高孕鼠血清TBA水平(P<0.05)，激活ERS标志物及炎症因子，并下调胆汁酸转运蛋白和合成限速酶CYP7A1的表达(均P<0.05)。4-PBA干预有效抑制ERS，降低TBA水平(P<0.05)，并上调Ntcp、Bsep、Mdr3及Mrp3基因表达(均P<0.05)。结论 ERS在LPS干扰妊娠期胆汁酸代谢稳态中发挥重要作用，抑制ERS可通过调控胆汁酸转运蛋白改善胆汁淤积，为ICP的靶向治疗提供理论依据。
Abstract：Objective To explore the ameliorative effect of the endoplasmic reticulum stress inhibitor 4-phenylbutyric acid(4-PBA) on bile acid metabolism disorders induced by bacterial lipopolysaccharide(LPS) in latepregnant mice, and to clarify the regulatory mechanism of endoplasmic reticulum stress(ERS) in intrahepatic cholestasis of pregnancy(ICP).Methods Twenty-four pregnant mice were divided into control group, LPS group, 4-PBA group, and LPS+4-PBA group. On the 16th day of pregnancy, the LPS group received intraperitoneal injection of LPS(200 μg/kg) and the 4-PBA group received injection of 4-PBA(150 mg/kg). In the LPS+4-PBA group, 4-PBA was intraperitoneally injected first, followed by LPS administration 1 h later. Serum total bile acid(TBA), liver injury markers, bile acid profiles, and the expression of key genes and proteins were detected 6 h after LPS treatment.Results LPS exposure increased serum TBA levels in pregnant mice(P<0. 05), activated ERS markers and inflammatory factors, and downregulated bile acid transporters and the expression of the rate limiting enzyme CYP7A1(all P<0. 05). 4-PBA intervention effectively inhibited ERS, reduced TBA levels(P<0. 05), and upregulated Ntcp, Bsep, Mdr3, and Mrp3 gene expression(all P<0. 05).Conclusion ERS plays an important role in LPS interference with the homeostasis of bile acid metabolism during pregnancy. Inhibiting ERS can improve bile stasis by regulating bile acid transporters, providing a theoretical basis for targeted therapy of ICP.
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基本信息:
DOI：10.19405/j.cnki.issn1000-1492.2026.07.004
中图分类号:R714.255
引用信息:
[1]梁心茹,孙影,暴双蕊,等.4-苯基丁酸改善脂多糖引起的母鼠胆汁酸代谢紊乱[J].安徽医科大学学报,2026,61(07):1183-1190.DOI:10.19405/j.cnki.issn1000-1492.2026.07.004.
基金信息:
国家自然科学基金项目(编号：82073566); 安徽省自然科学基金项目(编号：2008085MH280); 安徽省高校中青年教师培养行动项目(编号：DTR2023012)~~
2026-05-26
2026-05-26
2026-05-26