Traditional Chinese medicine Lingguizhugan decoction ameliorate HFD-induced hepatic-lipid deposition in mice by inhibiting STING-mediated inflammation in macrophages.
Traditional Chinese medicine Lingguizhugan decoction ameliorate HFD-induced hepatic-lipid deposition in mice by inhibiting STING-mediated inflammation in macrophages.
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中药苓桂术甘汤通过抑制STING介导的巨噬细胞炎症改善HFD诱导的小鼠肝脏脂质沉积
DOI：
10.1186/s13020-021-00559-3
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发表时间：
2022-01-05
期刊：
影响因子：
4.9
通讯作者：
Liu C
中科院分区：
文献类型：
--
作者：
Cao L;Xu E;Zheng R;Zhangchen Z;Zhong R;Huang F;Ye J;Sun H;Fan Y;Xie S;Chen Y;Xu Y;Cao J;Cao W;Liu C
背景干扰素刺激因子基因（STING）在非酒精性脂肪性肝病（NAFLD）患者和高脂饮食（HFD）诱导的NAFLD小鼠模型肝脏中高表达。STING信号介导的炎症已被证明在代谢紊乱中起关键作用。苓桂术甘汤是一种治疗代谢性疾病的中药汤剂，临床应用已有多年。然而，LGZG是否能通过抑制炎症减轻NAFLD的进展仍不清楚。本研究旨在探讨STING介导的炎症在LGZG治疗HFD诱导的肝脏脂质沉积中的作用。方法采用H&E染色、免疫荧光和免疫化学方法检测LGZG的抗炎和抗脂肪变性作用。用STING特异性激动剂（DMXAA）、LGZG及其关键组分分别作用于小鼠骨髓源巨噬细胞（BMDMs）和原代肝巨噬细胞。将各组小鼠骨髓基质细胞和原代肝巨噬细胞培养上清分别与棕榈酸处理的小鼠原代肝细胞或小鼠肝细胞系AML-12共培养，检测LGZG抗脂肪变性作用中是否涉及STING途径的激活。采用油红染色法检测肝细胞在体内外的脂质沉积情况。采用真实的时间PCR检测小鼠肝提取液线粒体DNA的释放。结果LGZG能显著减轻HFD诱导的小鼠肝脏脂肪变性、氧化应激、肝线粒体损伤和线粒体DNA释放，其机制与降低HFD小鼠肝脏STING表达水平、减少STING阳性巨噬细胞浸润有关。LGZG的关键组分直接抑制DMXAA、LPS诱导的肝巨噬细胞STING-TBK 1-NF-κB通路的激活，从而减少IFNβ和TNFα的释放。结论LGZG可通过抑制肝巨噬细胞STING-TBK 1-NF-κB通路减轻HFD诱导的肝脂肪变性，为阐明LGZG减轻HFD诱导的肝脂肪变性的分子机制提供了新的思路。
BackgroundStimulator of IFN genes (STING) is highly expressed in the livers of non-alcoholic fatty liver disease (NAFLD) patients and high fat diet (HFD) induced NAFLD mice model. The STING signaling-mediated inflammation has been shown to play a critical role in metabolic disorders. Lingguizhugan decoction (LGZG), a Traditional Chinese herbal decoction, has been applied to treat metabolic disorders for many years. However, whether LGZG can alleviate the progression of NAFLD through inhibiting inflammation remains unclear. This study was to determine the role of STING-mediated inflammation in the HFD-induced hepatic-lipid deposition treated with LGZG.MethodsThe anti-inflammatory and anti-steatotic effects of LGZG in vivo were detected by H&E staining, immunofluorescence and immuno-chemistry. Mice bone-marrow-derived macrophages (BMDMs) and primary liver macrophages were treated with STING-specific agonist (DMXAA), LGZG and its critical components respectively. The treated culture supernatant of BMDMs and primary liver macrophages from each group was co-cultured with palmitic acid-treated mouse primary hepatocytes or mouse liver cell line AML-12 respectively to detect whether the activation of STING-mediated pathway is involved in the anti-steatotic effect of LGZG. The hepatocyte lipid deposition in vivo and in vitro were detected by oil red staining. Mitochondrial DNA release of mouse liver extracts were detected by real time PCR. The expression of proteins and inflammatory cytokines related to STING-TBK1-NF-κB pathway was detected by western blotting and ELISA.ResultsLGZG significantly ameliorated HFD induced hepatic steatosis, oxidative stress, hepatic mitochondrial damage and mitochondrial DNA release, which was correlated with reduction of the expression level of STING as well as the infiltration of STING-positive macrophages in the livers of HFD fed mice. The critical components of LGZG directly inhibited the activation of STING-TBK1-NF-κB pathway in liver macrophages induced by DMXAA, LPS, thereby reducing the release of IFNβ and TNFα. Co-incubating the culture supernatant of LGZG treated liver macrophages and PA-stimulated hepatocytes significantly inhibited the PA-induced lipid deposition.ConclusionThis study demonstrates that LGZG can ameliorate HFD-induced hepatic-lipid deposition through inhibiting STING-TBK1-NF-κB pathway in liver macrophages, which provides novel insight for elucidating the molecular mechanism of LGZG alleviating HFD induced hepatic steatosis.
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影响因子：
29.4
作者：
Cotter, Thomas G.;Rinella, Mary
通讯作者：
Rinella, Mary
影响因子：
29.4
作者：
Gehrke, Nadine;Schattenberg, Joern M.
通讯作者：
Schattenberg, Joern M.
DOI：
10.1038/nri3921
发表时间：
2015-12
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1161/atvbaha.117.309017
发表时间：
2017-05
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Mao Y;Luo W;Zhang L;Wu W;Yuan L;Xu H;Song J;Fujiwara K;Abe JI;LeMaire SA;Wang XL;Shen YH
通讯作者：
Shen YH
影响因子：
2.9
作者：
Guo, Lanfang;Ma, Ruili;Li, Zhengrong
通讯作者：
Li, Zhengrong