School of Pharmacy (W.Y., M.Z., B.L., L.L. C.X.), School of Basic Medicine (W.Y., C.W.), and Department of Pediatrics (F.Y.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and School of Pharmacy, Lanzhou University, Lanzhou, China (M.Z.).
School of Pharmacy (W.Y., M.Z., B.L., L.L. C.X.), School of Basic Medicine (W.Y., C.W.), and Department of Pediatrics (F.Y.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and School of Pharmacy, Lanzhou University, Lanzhou, China (M.Z.)
J Pharmacol Exp Ther. 2022 May;381(2):96-105. doi: 10.1124/jpet.121.001018. Epub 2022 Feb 27.
Resveratrol (RES), a natural polyphenol phytoalexin, has been reported to attenuate nonalcoholic fatty liver disease (NAFLD). However, its roles on protection of liver from lipotoxicity and underlying mechanism are not fully understood. In this study, we investigated the impacts of RES on alleviating hepatic lipotoxicity and corresponding molecular mechanism. Impacts of RES on oleic acid (OA)-induced lipotoxicity were assessed in L02 cells and C57BL/6J mice, respectively. In L02 cells, lipotoxicity was assessed by detection of apoptosis, mitochondrial function, oxidative stress and ROS-related signaling. In mice, lipotoxicity was evaluated by detecting hepatic function, serum enzyme activity, and reactive oxygen species (ROS) levels. We found that RES reduced OA-induced apoptosis, mitochondrial dysfunction, ROS generation, and DNA damage in L02 cells. RES also decreased expression of cleaved caspase-3 and p53 and increased expression of B-cell lymphoma 2 (Bcl-2). Importantly, RES protected mice from high-fat diet-induced hepatic lipotoxicity, demonstrated by reduced ROS levels and lipid peroxidation. Mechanically, B lymphoma Mo-MLV insertion region 1 (Bmi-1) expression and antioxidative superoxide dismutase were increased after RES treatment. Further mechanistic analysis indicated that protection effects of RES against OA-induced lipotoxicity were abrogated by Bmi-1 small interference RNA (siRNA) in L02 cells. SIGNIFICANCE STATEMENT: Results from clinical studies about the effect of RES on NAFLD are inconsistent and inconclusive. This study confirms the protective role of RES as an anti-ROS agent and its ability to alleviate DNA damage through a pathway involving p53/p21 signaling. Further mechanistic analysis indicated that protection effects of RES were relative with Bmi-1. This is the first study on the role of Bmi-1 in the pathogenesis of NAFLD and the target of resveratrol against NAFLD.
白藜芦醇（RES）是一种天然多酚植物抗毒素，据报道可减轻非酒精性脂肪性肝病（NAFLD）。然而，其保护肝脏免受脂毒性的作用及其潜在机制尚未完全阐明。在这项研究中，我们研究了 RES 减轻肝脂毒性的作用及其潜在机制。分别在 L02 细胞和 C57BL/6J 小鼠中评估 RES 对油酸（OA）诱导的脂毒性的影响。在 L02 细胞中，通过检测细胞凋亡、线粒体功能、氧化应激和 ROS 相关信号来评估脂毒性。在小鼠中，通过检测肝功能、血清酶活性和活性氧（ROS）水平来评估脂毒性。我们发现 RES 降低了 OA 诱导的 L02 细胞凋亡、线粒体功能障碍、ROS 生成和 DNA 损伤。RES 还降低了 cleaved caspase-3 和 p53 的表达，增加了 B 细胞淋巴瘤 2（Bcl-2）的表达。重要的是，RES 减轻了高脂肪饮食诱导的小鼠肝脂毒性，表现为 ROS 水平和脂质过氧化降低。机制上，RES 处理后 B 淋巴瘤 Mo-MLV 插入区 1（Bmi-1）表达和抗氧化超氧化物歧化酶增加。进一步的机制分析表明，在 L02 细胞中，Bmi-1 小干扰 RNA（siRNA）可阻断 RES 对 OA 诱导的脂毒性的保护作用。临床研究关于 RES 对 NAFLD 影响的结果不一致且尚无定论。本研究证实了 RES 作为一种抗 ROS 剂的保护作用及其通过 p53/p21 信号通路减轻 DNA 损伤的能力。进一步的机制分析表明，RES 的保护作用与 Bmi-1 有关。这是关于 Bmi-1 在 NAFLD 发病机制中的作用以及 RES 针对 NAFLD 的靶点的第一项研究。
