Cardiolipin inhibitor ameliorates the non-alcoholic steatohepatitis through suppressing NLRP3 inflammasome activation.

脂肪性肝炎 脂肪肝 炎症体 酒精性肝病 脂肪变性 肝硬化 化学 酒精性肝炎 医学 心磷脂 肝病 炎症 内分泌学 肝损伤 癌症研究 内科学 疾病 生物化学 磷脂
作者
Jing Liu,T Wang,Kui He,Meiqing Xu,JP Gong
出处
期刊:PubMed 卷期号:23 (18): 8158-8167 被引量:17
标识
DOI:10.26355/eurrev_201909_19036
摘要

Non-alcoholic fatty liver disease (NAFLD) has been proven to be the most common liver disease in the world, which is a sterile liver disease and is characterized by chronic hepatic steatosis and inflammation. The first step of the spectrum of the disease is the non-alcoholic fatty liver (NAFL). Based on hepatocellular necrosis and inflammation, NAFL will progress to non-alcoholic steatohepatitis (NASH), which may have the potential to progress cirrhosis, and even hepatocellular carcinoma (HCC) in a few years. Kupffer cells (KCs) are liver-resident macrophages and have been proven to play a crucial role in NAFLD development. Cardiolipin is reported to be effective to trigger the activation of NLRP3 inflammasome through a ROS-independent signaling pathway. However, the exact mechanism of NLRP3 inflammasome activated by cardiolipin in KCs is still unclear.To make clear of the specific mechanism mentioned above, we firstly used a MCD-induced NASH mice model to demonstrate that CLS1 suppression reduced hepatic steatosis and inflammation. Secondly, the results of IHC staining indicated that the expressions of CLS1 and NLRP3 in liver tissues were significantly upregulated in the NASH group compared to the ND group. On the contrary, CLS1 inhibition significantly downregulated NLRP3 expression in liver tissues, which indicated that CLS1 probably regulated the level of NLRP3 expression. Furthermore, we demonstrated that CLS1 suppression significantly ameliorated the liver function and decreased the TG level, and interleukin-1β (IL-1β) and IL-18 were markedly reduced upon CLS1 inhibition.In this work, we reported that cardiolipin is involved in the development of NASH, and the suppression of the cardiolipin synthesis by shRNA-CLS1 could ameliorate the hepatic pathogenic manifestations, as well as the serum inflammatory biomarkers. We further showed that the protein expressions of CLS1, NLRP3, ASC, and Caspase-1 were all upregulated in the NASH liver tissues and palmitic stimulated KCs.Our study showed that the upregulation of NLRP3 inflammasome activated by cardiolipin is crucial in NASH pathogenesis, which might provide a novel potential role of cardiolipin blockade in the treatment of NASH.
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