Baicalin improved hepatic injury of NASH by regulating NRF2/HO-1/NRLP3 pathway
Baicalin improved hepatic injury of NASH by regulating NRF2/HO-1/NRLP3 pathway
复制标题
黄芩苷通过调节NRF2/HO-1/NRLP3通路改善NASH肝损伤
DOI：
10.1016/j.ejphar.2022.175270
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发表时间：
2022-09-29
影响因子：
5
通讯作者：
Chen, Yuanyuan
中科院分区：
文献类型：
--
作者：
Shi, Huilian;Qiao, Fei;Chen, Yuanyuan
非酒精性脂肪性肝炎（nonalcoholic steatohepatitis，NASH）处于非酒精性脂肪性肝病（nonalcoholic fatty liver disease，NAFLD）的重要病理阶段和治疗关键期，与肝纤维化、肝细胞癌和肝癌相关，已成为严重的医学问题。黄芩苷是黄芩的主要有效成分之一，具有抗氧化和抗炎活性。然而，其对NASH的影响及其潜在的分子机制尚未完全了解。在前期的研究中，我们已经阐明了黄芩苷在体外可以抑制NLRP 3介导的肝细胞凋亡，但体内验证和上游机制仍需进一步研究。在此，通过用高脂肪饮食（HFD）喂养8-12周来诱导NASH小鼠模型。此后，在接下来的几周内，NASH小鼠给予HFD加黄芩苷。随后，我们检查了他们的肝功能和炎症反应，并进行了肝脏标本的HE染色。此外，通过多种分子生物学实验，包括定量实时PCR（qRT-PCR）、蛋白质印迹（WB）、siRNA和CCK 8检测，在与游离脂肪酸孵育的HepG 2细胞中揭示了潜在的分子机制，并在NASH小鼠中得到验证。体内研究结果表明，黄芩苷可降低NASH小鼠肝组织中的脂质积聚和炎症，表现为NRF 2/HO-1表达增强和NLRP 3/Caspase 1/GSDMD水平降低，这些因素参与了肝细胞凋亡途径。同时黄芩苷对氧化损伤也有明显的保护作用。体外实验证实了黄芩苷的抗炎作用。另一方面，NRF 2基因的敲低明显减弱了黄芩苷的保护作用，降低了NLRP 3/Caspase 1/GSDMD介导的肝细胞凋亡，表明黄芩苷能够通过调节NRF 2/HO-1/NRLP 3通路减轻NASH肝细胞凋亡。
Being at the important pathological stage and the critical treatment period of non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) which is associated with fibrosis, hepatic and liver cancer has become a serious medical problem. As one of the major effective components in Scutellaria baicalensis, baicalin takes on anti-oxidant and anti-inflammatory activities. Nevertheless, its effects on NASH and its underlying molecular mechanism have not been thoroughly understood yet. In previous study, we have clarified baicalin could inhibit pyroptosis of hepatocytes mediated by NLRP3 in vitro, but the verification in vivo and upstream mechanism still need further work. Here the NASH mouse model was induced by feeding with a high fat diet (HFD) for 8-12 weeks. Thereafter, in the following weeks, NASH mice were given with HFD plus baicalin. We, subsequently, examined their hepatic function and inflammatory response and conducted the HE staining of liver samples. Furthermore, the underlying molecular mechanism was revealed through diverse molecular biological experiments including quantitative real-time PCR (qRT-PCR), Western blotting (WB), siRNA and CCK8 assays in HepG2 cells incubated with free fatty acid, and was verified in NASH mice. The in vivo findings indicated that baicalin decreased lipid accumulation and inflammation in the liver tissues of NASH mice, as evidenced by the enhanced NRF2/HO-1 expression and the reduced NLRP3/Caspase1/GSDMD levels, and these factors were involved in the pyroptosis pathway. Meanwhile, baicalin also contributed greatly against oxidative injury. The anti-inflammatory effect of baicalin was confirmed by experiments in vitro. For another, knockdown of NRF2 obviously weakened the protective effects of baicalin and reduced the NLRP3/Caspase1/GSDMD-mediated pyroptosis.This study indicates that baicalin is able to attenuate hepatic cell pyroptosis in vivo and in vitro in the case of NASH by regulating the NRF2/HO-1/NRLP3 pathway.