Celastrol attenuates mitochondrial dysfunction and inflammation in palmitate-mediated insulin resistance in C3A hepatocytes
Celastrol attenuates mitochondrial dysfunction and inflammation in palmitate-mediated insulin resistance in C3A hepatocytes
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DOI：
10.1016/j.ejphar.2017.01.043
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发表时间：
2017-03-15
影响因子：
5
通讯作者：
Rosdi, Mohamad Norisham Mohamad
中科院分区：
文献类型：
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作者：
Abu Bakar, Mohamad Hafizi;Sarmidi, Mohamad Roji;Rosdi, Mohamad Norisham Mohamad
越来越多的证据表明，线粒体功能障碍诱导的炎症是肝脏胰岛素抵抗最大标志的汇聚点之一。南蛇藤酚是一种来自雷公藤根的抗炎化合物，据报道可以减轻动物疾病模型中的胰岛素抵抗和炎症。然而，雷公藤红素在细胞水平上调节这种改善的具体机制作用仍然不清楚。本研究旨在探讨雷公藤红素对软脂酸诱导的C3 A人肝细胞胰岛素抵抗的作用机制。暴露于棕榈酸（0.75 mM）48 h的肝细胞表现出基础和胰岛素刺激的葡萄糖摄取减少，线粒体功能障碍，导致线粒体氧化应激增加，脂肪酸氧化减少。棕榈酸酯治疗后，观察到核因子-κ B p65（NF-κ B p65）、c-Jun NH（2）-末端激酶（JNK）信号通路的表达升高以及促炎细胞因子（包括IL-8、IL-6、TNF-α和CRP）的释放增加。同时，棕榈酸酯减少和增加磷酸化的酪氨酸-612和丝氨酸-307胰岛素受体底物-1（IRS-1）蛋白，分别在肝细胞。然而，30 nM的最佳浓度的雷公藤红素能够逆转这些有害的情况，并保护细胞免受线粒体功能障碍和胰岛素抵抗。重要的是，我们首次提出了雷公藤红素至少通过改善线粒体功能和胰岛素信号通路有效预防肝细胞中棕榈酸诱导的胰岛素抵抗的证据。总之，本研究强调了一种可能的机制，以阐明雷公藤红素在减轻线粒体功能障碍和炎症对肝胰岛素抵抗的发展的细胞保护潜力。
Accumulating evidence indicates that mitochondrial dysfunction-induced inflammation is among the convergence points for the greatest hallmarks of hepatic insulin resistance. Celastrol, an anti-inflammatory compound from the root of Tripterygium Wilfordii has been reported to mitigate insulin resistance and inflammation in animal disease models. Nevertheless, the specific mechanistic actions of celastrol in modulating such improvements at the cellular level remain obscure. The present study sought to explore the mechanistic roles of celastrol upon insulin resistance induced by palmitate in C3A human hepatocytes. The hepatocytes exposed to palmitate (0.75 mM) for 48 h exhibited reduced both basal and insulin-stimulated glucose uptake, mitochondrial dysfunction, leading to increased mitochondrial oxidative stress with diminished fatty acid oxidation. Elevated expressions of nuclear factor-kappa B p65 (NF-kappa B p65), c-Jun NH(2)-terminal kinase (JNK) signaling pathways and the amplified release of pro-inflammatory cytokines including IL-8, IL-6, TNF-alpha and CRP were observed following palmitate treatment. Consistently, palmitate reduced and augmented phosphorylated Tyrosine-612 and Serine-307 of insulin receptor substrate-1 (IRS-1) proteins, respectively in hepatocytes. However, celastrol at the optimum concentration of 30 nM was able to reverse these deleterious occasions and protected the cells from mitochondrial dysfunction and insulin resistance. Importantly, we presented evidence for the first time that celastrol efficiently prevented palmitate-induced insulin resistance in hepatocytes at least, via improved mitochondrial functions and insulin signaling pathways. In summary, the present investigation underlines a conceivable mechanism to elucidate the cytoprotective potential of celastrol in attenuating mitochondrial dysfunction and inflammation against the development of hepatic insulin resistance.