Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, 317000, China.
Department of Hepatobiliary Surgery, Liaocheng People's Hospital, Liaocheng, Shandong, 252000, China.
Biochem Biophys Res Commun. 2019 Jun 25;514(2):372-378. doi: 10.1016/j.bbrc.2019.04.144. Epub 2019 Apr 28.
Multiple molecular events are involved in non-alcoholic steatohepatitis (NASH). There is no consensus on the role of inducible nitric oxide synthase (iNOS) in the progression of NASH. The present study therefore investigated the role of iNOS in NASH pathogenesis using bone marrow-transplanted iNOS chimeric mice under high-fat diet (HFD) conditions. The chimeric mice were fed a HFD for 16 wk, and primary hepatocytes were stimulated with oleic acid (OA). The molecular mechanisms underlying the role of iNOS in NASH were investigated. Marked hepatic steatosis and injury observed in the HFD mice and OA-stimulated hepatocytes were reduced by hepatocyte-derived iNOS. Mechanistically, iNOS upregulated heme oxygenase 1 (HO-1) by augmenting nuclear factor erythroid 2-related factor 2 (Nrf-2) binding to the HO-1 gene promoter. In conclusion, hepatocyte-derived iNOS may play a protective role against the progression of NASH by upregulating HO-1 through Nrf-2. Upregulation of hepatocellular iNOS may represent a potentially new therapeutic paradigm to combat NASH.
多种分子事件参与非酒精性脂肪性肝炎（NASH）的发生。诱导型一氧化氮合酶（iNOS）在 NASH 的进展中的作用尚无共识。因此，本研究使用高脂肪饮食（HFD）条件下的骨髓移植 iNOS 嵌合小鼠，研究了 iNOS 在 NASH 发病机制中的作用。嵌合小鼠接受 HFD 喂养 16 周，并使用油酸（OA）刺激原代肝细胞。研究了 iNOS 在 NASH 中的作用的分子机制。HFD 小鼠和 OA 刺激的肝细胞中观察到的明显肝脂肪变性和损伤，通过肝细胞来源的 iNOS 减少。从机制上讲，iNOS 通过增强核因子红细胞 2 相关因子 2（Nrf-2）与 HO-1 基因启动子的结合而上调血红素加氧酶 1（HO-1）。总之，肝细胞来源的 iNOS 可能通过 Nrf-2 上调 HO-1 发挥保护作用，防止 NASH 的进展。肝细胞内 iNOS 的上调可能代表一种对抗 NASH 的潜在新的治疗范例。
