Li Qiao-Ping, Dou Yao-Xing, Huang Zi-Wei, Chen Han-Bin, Li Yu-Cui, Chen Jian-Nan, Liu Yu-Hong, Huang Xiao-Qi, Zeng Hui-Fang, Yang Xiao-Bo, Su Zi-Ren, Xie Jian-Hui
School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China.
The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China.
Phytomedicine. 2021 May;85:153550. doi: 10.1016/j.phymed.2021.153550. Epub 2021 Mar 17.
Berberine (BBR) has been widely used to treat non-alcoholic fatty liver disease (NAFLD). The metabolites of BBR were believed to contribute significantly to its pharmacological effects. Oxyberberine (OBB), a gut microbiota-mediated oxidative metabolite of BBR, has been firstly identified in our recent work.
Here, we aimed to comparatively investigate the anti-NAFLD properties of OBB and BBR.
The anti-NAFLD effect was evaluated in high-fat diet-induced obese NAFLD rats with biochemical/ELISA tests and histological staining. The related gene and protein expressions were detected by qRT-PCR and Western blotting respectively. Molecular docking and dynamic simulation were also performed to provide further insight.
Results indicated OBB remarkably and dose-dependently attenuated the clinical manifestations of NAFLD, which (100 mg/kg) achieved similar therapeutic effect to metformin (300 mg/kg) and was superior to BBR of the same dose. OBB significantly inhibited aberrant phosphorylation of IRS-1 and up-regulated the downstream protein expression and phosphorylation (PI3K, p-Akt/Akt and p-GSK-3β/GSK-3β) to improve hepatic insulin signal transduction. Meanwhile, OBB treatment remarkably alleviated inflammation via down-regulating the mRNA expression of MCP-1, Cd68, Nos2, Cd11c, while enhancing Arg1 mRNA expression in white adipose tissue. Moreover, OBB exhibited closer affinity with AMPK in silicon and superior hyperphosphorylation of AMPK in vivo, leading to increased ACC mRNA expression in liver and UCP-1 protein expression in adipose tissue.
Taken together, compared with BBR, OBB was more capable of maintaining lipid homeostasis between liver and WAT via attenuating hepatic insulin pathway and adipocyte inflammation, which was associated with its property of superior AMPK activator.
黄连素（BBR）已被广泛用于治疗非酒精性脂肪性肝病（NAFLD）。人们认为BBR的代谢产物对其药理作用有显著贡献。氧化小檗碱（OBB）是BBR经肠道微生物群介导的氧化代谢产物，我们在最近的研究中首次鉴定出该物质。
在此，我们旨在比较研究OBB和BBR的抗NAFLD特性。
通过生化/酶联免疫吸附测定试验和组织学染色，在高脂饮食诱导的肥胖NAFLD大鼠中评估抗NAFLD作用。分别通过qRT-PCR和蛋白质免疫印迹法检测相关基因和蛋白质表达。还进行了分子对接和动态模拟以提供进一步的见解。
结果表明，OBB显著且剂量依赖性地减轻了NAFLD的临床表现，其（100mg/kg）达到了与二甲双胍（300mg/kg）相似的治疗效果，且优于相同剂量的BBR。OBB显著抑制IRS-1的异常磷酸化，并上调下游蛋白质表达和磷酸化（PI3K、p-Akt/Akt和p-GSK-3β/GSK-3β），以改善肝脏胰岛素信号转导。同时，OBB治疗通过下调MCP-1、Cd68、Nos2、Cd11c的mRNA表达，显著减轻炎症，同时增强白色脂肪组织中Arg1 mRNA表达。此外，OBB在硅中与AMPK表现出更紧密的亲和力，且在体内具有更高的AMPK磷酸化水平，导致肝脏中ACC mRNA表达增加和脂肪组织中UCP-1蛋白表达增加。
综上所述，与BBR相比，OBB更能够通过减弱肝脏胰岛素途径和脂肪细胞炎症来维持肝脏和白色脂肪组织之间的脂质稳态，这与其作为优越的AMPK激活剂的特性有关。
