Abstract：
Previous studies have shown that oxyberberine (OBB), a novel gut microbiota metabolite of berberine, exhibited prominent protective property against acute liver injury and non-alcoholic fatty liver diseases, however, the effect of OBB on liver fibrosis and its potential mechanisms remain largely unknown. This study was aimed to study the effects of OBB on carbon tetrachloride (CCl4)-induced liver fibrosis and tried to clarify the potential mechanisms by focusing on regulating of sirtuin 3 (SIRT3)-mediated liver inflammation. OBB significantly alleviated the liver injury and fibrosis in CCl4-treated C57/BL6 mouse livers. OBB evidently down-regulated the expression of inflammatory factors and reduced the levels of inflammatory factors in CCl4-treated mouse livers. Noteworthy, CCl4-treated decreased the mRNA and protein expression of SIRT3, and treatment with OBB notably increased the expression of SIRT3 both in transcriptional and translational levels in CCl4-treated mice livers. OBB also suppressed the cell viability of TGF-β1-stimulated JS-1 cells and inhibited the protein expression of α-SMA but increased the expression of SIRT3 in stimulated JS-1 cells. Moreover, depletion of SIRT3 weakened the anti-inflammatory effects of OBB in stimulated JS-1 cells. Interestingly, the anti-liver injury and anti-fibrotic effects of OBB could be available in CCl4-treated WT (129S1/SvImJ) mice but were unavailable in CCl4-treated SIRT3 knockout (KO) mice. In addition, the anti-inflammatory effect of OBB was only found in CCl4-treated WT mice but was not in SIRT3 KO mice. Collectively, these findings suggested that OBB suppressed the liver injury and fibrosis through inhibition of liver inflammation in a SIRT3-dependent manner in CCl4-treated mice.
摘要：
以前的研究表明，羟色胺（OBB），小檗碱的一种新型肠道微生物代谢产物，对急性肝损伤和非酒精性脂肪性肝病表现出突出的保护特性，然而,OBB对肝纤维化的影响及其潜在机制仍在很大程度上未知。本研究旨在研究OBB对四氯化碳（CCl4）诱导的肝纤维化的影响，并试图通过调节沉默酶3（SIRT3）介导的肝脏炎症来阐明其潜在机制。OBB可显着减轻CCl4处理的C57/BL6小鼠肝脏的肝损伤和纤维化。OBB明显下调CCl4处理的小鼠肝脏中炎症因子的表达并降低炎症因子的水平。值得注意的是,CCl4处理降低了SIRT3的mRNA和蛋白质表达，而OBB处理显着增加了CCl4处理的小鼠肝脏中SIRT3的转录和翻译水平的表达。OBB还抑制TGF-β1刺激的JS-1细胞的细胞活力，并抑制α-SMA的蛋白表达，但增加SIRT3在刺激的JS-1细胞中的表达。此外，SIRT3的消耗削弱了OBB在刺激的JS-1细胞中的抗炎作用。有趣的是,在CCl4治疗的WT(129S1/SvImJ)小鼠中,OBB的抗肝损伤和抗纤维化作用是可行的,但在CCl4治疗的SIRT3基因敲除(KO)小鼠中不可用.此外,OBB的抗炎作用仅在CCl4治疗的WT小鼠中发现，而在SIRT3KO小鼠中没有。总的来说，这些发现表明，在CCl4处理的小鼠中，OBB通过抑制肝脏炎症以SIRT3依赖性方式抑制肝脏损伤和纤维化。
