Cielica Eliza, Łaba Alicja, Milkiewicz Piotr, Kruk Beata, Kempinska-Podhorodecka Agnieszka, Kłos Patrycja, Rodrigues Pedro M, Val Beatriz, Perugorria Maria J, Banales Jesus M, Milkiewicz Malgorzata
Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland.
Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 02-097 Warsaw, Poland.
Cells. 2025 Jul 23;14(15):1137. doi: 10.3390/cells14151137.
Ursodeoxycholic acid (UDCA) is widely used to treat cholestatic liver diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), yet its molecular mechanisms remain unclear. This study investigated the impact of long-term UDCA therapy on circulating levels of the microRNAs miR-34a and miR-506, which are implicated in PBC pathogenesis, and explored associated changes in inflammatory markers and signaling pathways. Serum samples from patients with PBC and PSC were collected before and after UDCA treatment and analyzed for miRNA expression as well as levels of TREM-2 and sCD163. In vitro studies using human cholangiocytes and lipopolysaccharide (LPS) stimulation assessed changes in the expression of miR-34a, TREM-2, and ADAM17. The results showed that the baseline levels of miR-34a and miR-506 were significantly elevated in PBC patients compared to controls and were significantly reduced after UDCA therapy in PBC but not in PSC. UDCA also decreased serum levels of TREM-2 and sCD163. In vitro, it suppressed the LPS-induced expression of miR-34a and ADAM17 while enhancing TREM-2 expression. Single-cell RNA sequencing of liver tissue and immunofluorescence staining confirmed TREM-2 expression in cholangiocytes. These findings suggest that UDCA modulates key inflammatory pathways and miRNAs in PBC, providing mechanistic insights into its therapeutic effect.
熊去氧胆酸（UDCA）被广泛用于治疗胆汁淤积性肝病，如原发性胆汁性胆管炎（PBC）和原发性硬化性胆管炎（PSC），但其分子机制仍不清楚。本研究调查了长期UDCA治疗对参与PBC发病机制的微小RNA miR-34a和miR-506循环水平的影响，并探讨了炎症标志物和信号通路的相关变化。收集PBC和PSC患者在UDCA治疗前后的血清样本，分析miRNA表达以及TREM-2和sCD163水平。使用人胆管细胞和脂多糖（LPS）刺激进行的体外研究评估了miR-34a、TREM-2和ADAM17表达的变化。结果显示，与对照组相比，PBC患者中miR-34a和miR-506的基线水平显著升高，PBC患者在UDCA治疗后显著降低，但PSC患者未降低。UDCA还降低了血清TREM-2和sCD163水平。在体外，它抑制了LPS诱导的miR-34a和ADAM17表达，同时增强了TREM-2表达。肝组织的单细胞RNA测序和免疫荧光染色证实了胆管细胞中TREM-2的表达。这些发现表明，UDCA调节PBC中的关键炎症通路和微小RNA，为其治疗效果提供了机制性见解。
