S-adenosyl-L-methionine is an endogenous molecule with hepato-protective properties linked to redox regulation and methylation. Here, the potential therapeutic value of SAMe was tested in 17 patients with PBC, a cholestatic disease with autoimmune phenomena targeting small bile ducts. Nine patients responded to SAMe (SAMe responders) with increased serum protein S-glutathionylation. That posttranslational protein modification was associated with reduction of serum anti-mitochondrial autoantibodies (AMA-M2) titers and improvement of liver biochemistry. Clinically, SAMe responders were younger at diagnosis, had longer duration of the disease and lower level of serum S-glutathionylated proteins at entry. SAMe treatment was associated with negative correlation between protein S-glutathionylation and TNFα. Furthermore, AMA-M2 titers correlated positively with INFγ and FGF-19 while negatively with TGFβ. Additionally, cirrhotic PBC livers showed reduced levels of glutathionylated proteins, glutaredoxine-1 (Grx-1) and GSH synthase (GS). The effect of SAMe was also analyzed in vitro. In human cholangiocytes overexpressing miR-506, which induces PBC-like features, SAMe increased total protein S-glutathionylation and the level of γ-glutamylcysteine ligase (GCLC), whereas reduced Grx-1 level. Moreover, SAMe protected primary human cholangiocytes against mitochondrial oxidative stress induced by tBHQ (tert-Butylhydroquinone) via raising the level of Nrf2 and HO-1. Finally, SAMe reduced apoptosis (cleaved-caspase3) and PDC-E2 (antigen responsible of the AMA-M2) induced experimentally by glycochenodeoxycholic acid (GCDC). These data suggest that SAMe may inhibit autoimmune events in patients with PBC via its antioxidant and S-glutathionylation properties. These findings provide new insights into the molecular events promoting progression of PBC and suggest potential therapeutic application of SAMe in PBC.

S-腺苷-L-蛋氨酸是一种内源性分子，具有与氧化还原调节和甲基化相关的肝保护特性。在这里，SAMe的潜在治疗价值在17例PBC患者中进行了测试，PBC是一种胆汁淤积性疾病，具有针对小胆管的自身免疫现象。九名患者对SAMe（SAMe应答者）的反应是血清蛋白S-谷胱甘肽化增加。翻译后蛋白质修饰与降低血清抗线粒体自身抗体（AMA-M2）滴度和改善肝脏生物化学有关。临床上，SAMe应答者在诊断时较年轻，病程较长，入院时血清S-谷胱甘肽化蛋白水平较低。SAMe治疗与蛋白S-谷胱甘肽酰化和TNFα负相关。此外，AMA-M2滴度与INFγ和FGF-19正相关，而与TGFβ负相关。此外，肝硬化的PBC肝脏的谷胱甘肽化蛋白，谷氨酸（Grx-1）和GSH合酶（GS）含量降低。还分析了SAMe的作用体外。在人类胆管细胞过表达miR-506（诱导PBC样特征）的过程中，SAMe增加了总蛋白S-谷胱甘肽化和γ-谷氨酰半胱氨酸连接酶（GCLC）的水平，而Grx-1的水平降低了。此外，SAMe通过提高Nrf2和HO-1的水平来保护人类原发性胆管细胞免受tBHQ（叔丁基对苯二酚）诱导的线粒体氧化应激。最后，SAMe减少了糖去氧胆酸（GCDC）实验诱导的凋亡（裂解的caspase3）和PDC-E2（负责AMA-M2的抗原）。这些数据表明，SAMe可能通过以下途径抑制PBC患者的自身免疫事件：其抗氧化剂和S-谷胱甘肽化特性。这些发现为促进PBC进程的分子事件提供了新见解，并暗示了SAMe在PBC中的潜在治疗应用。