Gu Xinnan, Wei Mengjuan, Hu Feifei, Ouyang Hao, Huang Zhenlin, Lu Bin, Ji Lili
The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Chem Biol Interact. 2023 May 1;376:110461. doi: 10.1016/j.cbi.2023.110461. Epub 2023 Mar 23.
Non-alcoholic steatohepatitis (NASH) is a severe pathological stage in non-alcoholic fatty liver disease (NAFLD) and is generally recognized to be induced by chronic inflammation. Natural compound chlorogenic acid (CGA) is well-known for its anti-inflammatory capacity. This study aimed at evaluating the alleviation of CGA on NASH and further exploring its engaged mechanism via focusing on abrogating hepatic inflammation. Our results showed that CGA had a good amelioration on NASH in vivo. CGA alleviated liver oxidative injury by inducing nuclear factor erythroid 2-related factor 2 (Nrf2) activation and reduced liver steatosis via up-regulating peroxisome proliferator-activated receptor-alpha (PPARα). CGA attenuated hepatic inflammation in vivo, but didn't decrease the elevated lipopolysaccharide (LPS) content. CGA blocked the activation of nuclear factor kappa-B (NFκB) or inflammasome both in MCDD-fed mice and in LPS-stimulated macrophages. CGA was found to directly bind to myeloid differentiation primary response 88 (MyD88), and thus competitively blocked the interaction between toll-like receptor 4 (TLR4) and MyD88, thereby abrogating hepatic inflammation initiated by LPS-TLR4-MyD88. Moreover, the CGA-provided anti-inflammatory effect was obviously disappeared in macrophages overexpressed MyD88. Hence, CGA has an excellent efficacy in improving NASH. CGA alleviated liver inflammation during NASH progression through blocking LPS-TLR4-MyD88 signaling pathway via directly binding to MyD88.
非酒精性脂肪性肝炎（NASH）是非酒精性脂肪性肝病（NAFLD）的严重病理阶段，通常认为是由慢性炎症诱导的。天然化合物绿原酸（CGA）以其抗炎能力而闻名。本研究旨在评估CGA对NASH的缓解作用，并通过关注消除肝脏炎症进一步探索其作用机制。我们的结果表明，CGA在体内对NASH有良好的改善作用。CGA通过诱导核因子红细胞2相关因子2（Nrf2）激活减轻肝脏氧化损伤，并通过上调过氧化物酶体增殖物激活受体α（PPARα）减少肝脏脂肪变性。CGA在体内减轻肝脏炎症，但并未降低升高的脂多糖（LPS）含量。CGA在MCDD喂养的小鼠和LPS刺激的巨噬细胞中均阻断核因子κB（NFκB）或炎性小体的激活。发现CGA直接与髓样分化初级反应88（MyD88）结合，从而竞争性阻断Toll样受体4（TLR4）与MyD88之间的相互作用，从而消除由LPS-TLR4-MyD88引发的肝脏炎症。此外，在过表达MyD88的巨噬细胞中，CGA提供的抗炎作用明显消失。因此，CGA在改善NASH方面具有优异的疗效。CGA通过直接与MyD88结合阻断LPS-TLR4-MyD88信号通路，减轻NASH进展过程中的肝脏炎症。
