Palmitic acid stimulates NLRP3 inflammasome activation through TLR4-NF-κB signal pathway in hepatic stellate cells
Palmitic acid stimulates NLRP3 inflammasome activation through TLR4-NF-κB signal pathway in hepatic stellate cells
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DOI：
10.21037/atm.2020.02.21
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发表时间：
2020-03-01
影响因子：
--
通讯作者：
Wan, Xinjian
中科院分区：
文献类型：
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作者：
Dong, Zhixia;Zhuang, Qian;Wan, Xinjian
背景：NLRP 3炎性小体激活在NASH和纤维化的发生发展中起重要作用。然而，参与肝星状细胞（HSC）中NLRP 3激活的机制尚不清楚。本研究旨在探讨NLRP 3在HSC中的活化机制以及NLPR 3炎性小体在非酒精性脂肪性肝炎（NASH）向纤维化发展中的作用。动物实验：4周龄SD大鼠喂饲高脂饲料12周，分别于0、4、8、12周处死。在另一组动物实验中，用HF-饮食和NLRP 3抑制剂（腹腔注射NLRP 3抑制剂格列本脲5 mg/kg，每3天注射一次）喂养4周龄SD大鼠12周。收集肝组织和血清。结果：软脂酸可刺激原代HSC中NLRP 3炎性小体的活化和纤维化表型的改变，LPS可使HSC对软脂酸的反应敏感。TLR 4-NF-κ B信号通路参与了棕榈酸暴露的HSC和HF饮食诱导的NASH中NLRP 3炎性体的激活。结论：软脂酸通过TLR 4-NF-κ B信号通路激活HSC中NLRP 3炎性小体。HSC中的NLRP 3炎性体活化加剧NASH向肝纤维化的发展。
Background: The NLRP3 inflammasome activation plays an important role in the development of NASH and fibrogenesis. However, the mechanisms involved in NLRP3 activation in hepatic stellate cells (HSCs) have been unclear. The aim of this study was to investigate the mechanism of NLRP3 activation in HSCs and the role of NLPR3 inflammasome activation in HSCs on the development of nonalcoholic steatohepatitis (NASH) to fibrosis.Methods: Primary IISCs isolated from SD rats were incubated with palmitic acid and/or LPS, respectively. For in vivo animal experiment, 4-week-old SD rats were fed with high fat diet (HF-diet) for 12 weeks, SD rats were sacrificed at 0, 4, 8 and 12 w. In another group of animal experiment, 4-week-old SD rats were fed with HF-diet and a NLRP3 inhibitor (intraperitoneal injection of NLRP3 inhibitor glybenclamide 5 mg/kg, injected every 3 days) for 12 weeks. Liver tissue and serum were harvested. RT-PCR, WB, ELISA, immunofluorescence and immunohistochemistry were performed to assess the NLRP3 inflammasome activation and signal molecules.Results: Palmitic acid stimulated NLPR3 inflammasome activation and fibrotic phenotype change in primary HSCs, LPS sensitizes the response of HSCs to palmitic acid. TLR4-NF-kappa B signal pathway was involved in NLRP3 inflammasome activation in palmitic acid-exposed HSCs and HF diet-induced NASH. It is evident that administration of NLRP3 inhibitor reduced the development of NASH to liver fibrosis in the NASH rat model.Conclusions: Palmitic acid stimulates NLRP3 inflammasome activation through the TLR4-NF-kappa B signal pathway in HSCs. NLRP3 inflammasome activation in HSCs exacerbates the development of NASH to liver fibrosis.