Li H B, Yang Y R Y, Mo Z J, Ding Y, Jiang W J
Department of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China.
Braz J Med Biol Res. 2015 May;48(5):440-6. doi: 10.1590/1414-431X20144238. Epub 2015 Mar 6.
The present study investigated the effect of silibinin, the principal potential anti-inflammatory flavonoid contained in silymarin, a mixture of flavonolignans extracted from Silybum marianum seeds, on palmitate-induced insulin resistance in C2C12 myotubes and its potential molecular mechanisms. Silibinin prevented the decrease of insulin-stimulated 2-NBDG (2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose) uptake and the downregulation of glutamate transporter type 4 (GLUT4) translocation in C2C12 myotubes induced by palmitate. Meanwhile, silibinin suppressed the palmitate-induced decrease of insulin-stimulated Akt Ser473 phosphorylation, which was reversed by wortmannin, a specific inhibitor of phosphatidylinositol-3-kinase (PI3K). We also found that palmitate downregulated insulin-stimulated Tyr632 phosphorylation of insulin receptor substrate 1 (IRS-1) and up-regulated IRS-1 Ser307 phosphorylation. These effects were rebalanced by silibinin. Considering several serine/threonine kinases reported to phosphorylate IRS-1 at Ser307, treatment with silibinin downregulated the phosphorylation of both c-Jun N-terminal kinase (JNK) and nuclear factor-κB kinase β (IKKβ), which was increased by palmitate in C2C12 myotubes mediating inflammatory status, whereas the phosphorylation of PKC-θ was not significantly modulated by silibinin. Collectively, the results indicated that silibinin prevented inhibition of the IRS-1/PI3K/Akt pathway, thus ameliorating palmitate-induced insulin resistance in C2C12 myotubes.
本研究调查了水飞蓟宾（水飞蓟素中的主要潜在抗炎类黄酮，水飞蓟素是从水飞蓟种子中提取的黄酮木脂素混合物）对棕榈酸诱导的C2C12肌管胰岛素抵抗的影响及其潜在分子机制。水飞蓟宾可防止棕榈酸诱导的C2C12肌管中胰岛素刺激的2-NBDG（2-[N-(7-硝基苯并-2-恶唑-1,3-二氮杂-4-基)氨基]-2-脱氧-D-葡萄糖）摄取减少以及4型谷氨酸转运体（GLUT4）转位的下调。同时，水飞蓟宾抑制了棕榈酸诱导的胰岛素刺激的Akt Ser473磷酸化降低，而渥曼青霉素（一种磷脂酰肌醇-3-激酶（PI3K）的特异性抑制剂）可逆转这种降低。我们还发现，棕榈酸下调了胰岛素刺激的胰岛素受体底物1（IRS-1）的Tyr632磷酸化，并上调了IRS-1 Ser307磷酸化。水飞蓟宾可使这些作用恢复平衡。考虑到有几种丝氨酸/苏氨酸激酶据报道可使IRS-1在Ser307位点磷酸化，水飞蓟宾处理下调了c-Jun氨基末端激酶（JNK）和核因子-κB激酶β（IKKβ）的磷酸化，在介导炎症状态的C2C12肌管中，棕榈酸可使二者磷酸化增加，而水飞蓟宾对蛋白激酶C-θ（PKC-θ）的磷酸化没有明显调节作用。总体而言，结果表明水飞蓟宾可防止IRS-1/PI3K/Akt途径受到抑制，从而改善棕榈酸诱导的C2C12肌管胰岛素抵抗。
