Effect of celastrol on toll‑like receptor 4‑mediated inflammatory response in free fatty acid‑induced HepG2 cells.
Effect of celastrol on toll‑like receptor 4‑mediated inflammatory response in free fatty acid‑induced HepG2 cells.
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DOI：
10.3892/ijmm.2018.3775
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发表时间：
2018-10
影响因子：
5.4
通讯作者：
Chen LM
中科院分区：
文献类型：
--
作者：
Han LP;Sun B;Li CJ;Xie Y;Chen LM
toll样受体4 （TLR4）介导的免疫和炎症信号在非酒精性脂肪性肝病（NAFLD）的发病机制中起关键作用。我们之前的研究表明，celastrol治疗能够改善2型糖尿病大鼠的肝脏脂肪变性，抑制TLR4信号级联通路。本研究旨在探讨雷公藤红素对脂肪变性HepG2细胞甘油三酯积累和炎症的影响，以及TLR4基因在体外被小干扰RNA （siRNA）敲低后调控细胞反应的可能机制。在不含或不含雷公藤红素的情况下，将HepG2细胞暴露于游离脂肪酸（FFA）中制备肝脂肪变性细胞模型。油红O染色显示细胞内甘油三酯，并研究TLR4/髓细胞分化主要反应88 (MyD88)/核因子-κB （NF-κB）信号级联通路。为了直接阐明TLR4是否是白藜芦醇在FFA暴露后的阻断靶点，我们通过转染TLR4 siRNA来测定细胞对炎症的反应。结果显示，celastrol可显著降低脂肪变性HepG2细胞中甘油三酯的积累，下调TLR4、MyD88、磷酸化nf -κBp65以及下游炎性细胞因子白介素-1β和肿瘤坏死因子α的表达水平。TLR4的下调也能减轻ffa诱导的炎症反应。此外，TLR4 siRNA和雷公藤红素联合治疗进一步降低了炎症介质的表达。这些结果表明，雷公藤红素部分通过抑制tlr4介导的脂肪变性HepG2细胞的免疫和炎症反应来发挥其保护作用。
Toll-like receptor 4 (TLR4)-mediated immune and inflammatory signaling serves a pivotal role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Our previous study demonstrated that celastrol treatment was able to improve hepatic steatosis and inhibit the TLR4 signaling cascade pathway in type 2 diabetic rats. The present study aimed to investigate the effects of celastrol on triglyceride accumulation and inflammation in steatotic HepG2 cells, and the possible mechanisms responsible for the regulation of cellular responses following TLR4 gene knockdown by small interfering RNA (siRNA) in vitro. A cell model of hepatic steatosis was prepared by exposing the HepG2 cells to free fatty acid (FFA) in the absence or presence of celastrol. Intracellular triglycerides were visualized by Oil red O staining, and the TLR4/myeloid differentiation primary response 88 (MyD88)/nuclear factor-κB (NF-κB) signaling cascade pathway were investigated. To directly elucidate whether TLR4 was the blocking target of celastrol upon FFA exposure, the cellular response to inflammation was determined upon transfection with TLR4 siRNA. The results revealed that celastrol significantly reduced triglyceride accumulation in the steatotic HepG2 cells, and downregulated the expression levels of TLR4, MyD88 and phospho-NF-κBp65, as well as of the downstream inflammatory cytokines interleukin-1β and tumor necrosis factor α. Knockdown of TLR4 also alleviated FFA-induced inflammatory response. In addition, co-treatment with TLR4 siRNA and celastrol further attenuated the expression of inflammatory mediators. These results suggest that celastrol exerts its protective effect partly via inhibiting the TLR4-mediated immune and inflammatory response in steatotic HepG2 cells.
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影响因子：
3.5
作者：
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通讯作者：
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影响因子：
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影响因子：
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通讯作者：
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影响因子：
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作者：
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影响因子：
5.6
作者：
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Crespo J