Department of General Surgery, Affiliated Maternity and Child Health Care Hospital of Nantong University, Nantong 226018, China.
Department of Operating Room, Affiliated Maternity and Child Health Care Hospital of Nantong University, Nantong 226018, China.
Int Immunopharmacol. 2023 Mar;116:109876. doi: 10.1016/j.intimp.2023.109876. Epub 2023 Feb 13.
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 (CCl)-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 CCl-treated C57/BL6 mouse livers. OBB evidently down-regulated the expression of inflammatory factors and reduced the levels of inflammatory factors in CCl-treated mouse livers. Noteworthy, CCl-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 CCl-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 CCl-treated WT (129S1/SvImJ) mice but were unavailable in CCl-treated SIRT3 knockout (KO) mice. In addition, the anti-inflammatory effect of OBB was only found in CCl-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 CCl-treated mice.
先前的研究表明，小檗红碱（OBB）是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具有显著的保护作用，然而，OBB 对肝纤维化的影响及其潜在机制仍知之甚少。本研究旨在研究 OBB 对四氯化碳（CCl）诱导的肝纤维化的影响，并通过聚焦于调节 SIRT3 介导的肝炎症来阐明潜在的机制。OBB 显著减轻 CCl 处理的 C57/BL6 小鼠肝脏的肝损伤和纤维化。OBB 明显下调炎症因子的表达，并降低 CCl 处理的小鼠肝脏中炎症因子的水平。值得注意的是，CCl 处理降低了 SIRT3 的 mRNA 和蛋白表达，而 OBB 处理在 CCl 处理的小鼠肝脏中显著增加了 SIRT3 的表达水平，无论是在转录水平还是翻译水平。OBB 还抑制了 TGF-β1 刺激的 JS-1 细胞的细胞活力，并抑制了刺激的 JS-1 细胞中α-SMA 的蛋白表达，但增加了 SIRT3 的表达。此外，SIRT3 的耗竭削弱了 OBB 在刺激的 JS-1 细胞中的抗炎作用。有趣的是，OBB 的抗肝损伤和抗纤维化作用在 CCl 处理的 WT（129S1/SvImJ）小鼠中是有效的，但在 CCl 处理的 SIRT3 敲除（KO）小鼠中无效。此外，OBB 的抗炎作用仅在 CCl 处理的 WT 小鼠中发现，而在 SIRT3 KO 小鼠中未发现。总之，这些发现表明，OBB 通过 SIRT3 依赖性方式抑制 CCl 处理的小鼠肝脏中的炎症来抑制肝损伤和纤维化。
