Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Pharmacology, Chongqing Medical University, Chongqing, China.
Department of Anatomy, Chongqing Medical University, Chongqing, China.
Free Radic Biol Med. 2024 Jan;210:42-53. doi: 10.1016/j.freeradbiomed.2023.11.011. Epub 2023 Nov 18.
Non-alcoholic steatohepatitis (NASH) is a prevalent metabolic disease, characterized by the hepatic steatosis, inflammation, and fibrosis, which is lack of effective treatment currently. Protectin D1 (PTD1), a lipid mediator from omega-3 fatty acid docosahexaenoic acid (DHA), has displayed wide pharmacological actions including anti-inflammation in a variety of diseases, but the role of PTD1 on NASH remains unclear. In this study, using the methionine and choline deficient (MCD) fed NASH model, we explored the effect and underlying mechanism of PTD1 on NASH in mice. Our results showed PTD1 improved MCD-induced steatosis, hepatocellular injury, inflammation and fibrosis. Furthermore, PTD1 inhibited MCD-induced activation of TLR4 downstream molecules (TAK1, p38 and p65) without affecting the levels of TLR4 and phosphorylated IRAK-1. Notably, the levels of IRAK-M protein and the binding between IRAK-M and TRAF6 in the liver were also increased by PTD1 in NASH mice. Moreover, IRAK-M knockout remarkedly reverted the beneficial effects of PTD1 on the NASH in mice. Thus, these results demonstrated that PTD1 could protect mice from NASH by inhibiting the activation of TLR4 downstream signaling pathway, which might be related to the upregulation of IRAK-M, indicating that PTD1 may provide a new treatment for NASH.
非酒精性脂肪性肝炎（NASH）是一种常见的代谢性疾病，其特征为肝脂肪变性、炎症和纤维化，但目前缺乏有效的治疗方法。保护素 D1（PTD1）是一种来源于ω-3 脂肪酸二十二碳六烯酸（DHA）的脂质介质，具有广泛的药理学作用，包括多种疾病的抗炎作用，但 PTD1 对 NASH 的作用尚不清楚。在本研究中，我们使用蛋氨酸和胆碱缺乏（MCD）喂养的 NASH 模型，探讨了 PTD1 对小鼠 NASH 的作用及其潜在机制。我们的结果表明，PTD1 改善了 MCD 诱导的脂肪变性、肝细胞损伤、炎症和纤维化。此外，PTD1 抑制了 MCD 诱导的 TLR4 下游分子（TAK1、p38 和 p65）的激活，而不影响 TLR4 和磷酸化 IRAK-1 的水平。值得注意的是，PTD1 还增加了 NASH 小鼠肝脏中 IRAK-M 蛋白的水平和 IRAK-M 与 TRAF6 的结合。此外，IRAK-M 敲除显著逆转了 PTD1 对小鼠 NASH 的有益作用。因此，这些结果表明，PTD1 通过抑制 TLR4 下游信号通路的激活来保护小鼠免受 NASH 的侵害，这可能与 IRAK-M 的上调有关，表明 PTD1 可能为 NASH 提供一种新的治疗方法。
