Pigment epithelium-derived factor (PEDF) ameliorates advanced glycation end product (AGE)-induced hepatic insulin resistance in vitro by suppressing Rac-1 activation
Pigment epithelium-derived factor (PEDF) ameliorates advanced glycation end product (AGE)-induced hepatic insulin resistance in vitro by suppressing Rac-1 activation
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DOI：
10.1055/s-0028-1083785
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发表时间：
2008-09-01
影响因子：
2.2
通讯作者：
Sata, M.
中科院分区：
文献类型：
--
作者：
Yoshida, T.;Yamagishi, S.;Sata, M.
晚期糖基化终产物(AGEs)可能与胰岛素抵抗有关。然而，其背后的分子机制还没有完全了解。由于色素上皮衍生因子(PEDF)阻断了AGE信号通路，我们在这里研究了低PEDF和低PEDF是否改善了暴露于AGE的肝癌细胞--Hep3B细胞的胰岛素抵抗。从Hep3B细胞中提取蛋白质，免疫沉淀法检测胰岛素受体底物-1(IRS-1)抗体，并进行免疫印迹分析。用[C-14]-D-葡萄糖测定糖原合成。AGE诱导Hep 3B细胞Rac-1活化，IRS-1丝氨酸-307位残基、JNK、c-jun和I kappa B激酶磷酸化增加，并伴随I kappa B水平降低。PEDF或显性阴性RAC-1的过表达可阻断AGE对Hep3B细胞的这些作用。此外，AGEs可降低胰岛素抵抗蛋白IRS-1的酪氨酸磷酸化水平，进而降低胰岛素暴露的Hep3B细胞中磷脂酰肌醇3-激酶P85亚单位与IRS-1和糖原合成的联系，这些都可被PEDF抑制。我们的研究表明，PEDF可能通过抑制RAC-1激活而抑制依赖JNK和I kappa B激酶的IRS-1丝氨酸磷酸化，从而改善AGE诱导的Hep3B细胞的胰岛素抵抗。PEDF对糖尿病患者肝脏胰岛素抵抗可能具有保护作用。
Advanced glycation end products (AGEs) Could be implicated ill insulin resistance. However, the molecular mechanisms underlying this are not fully understood. Since pigment epithelium-derived factor (PEDF) blocks the AGE-signaling pathways, we examined here whether and low PEDF improves insulin resistance ill AGE-exposed hepatoma cells, Hep3B cells. Proteins were extracted from Hep3B cells, immunoprecipitated with or without insulin receptor substrate-1 (IRS-1) antibodies, and subjected to Western blot analysis. Glycogen synthesis was measured using [C-14]-D-glucose. AGE induced Rac-1 activation and increased phosphorylation of IRS-1 at serine-307 residues, JNK, c-JUN, and I kappa B kinase in association with decreased I kappa B levels in Hep3B cells. PEDF or overexpression of dominant negative Rac-1 blocked these effects of AGE on Hep3B cells. Further, AGEs decreased tyrosine phosphorylation of IRS-1, and subsequently reduced the association of p85 subunit of phosphatidylinositol 3-kinase with IRS-1 and glycogen synthesis in insulin-exposed Hep3B cells, all of which were inhibited by PEDF Our present study suggests that PEDF could improve the AGE-elicited insulin resistance in Hep3B cells by inhibiting JNK- and I kappa B kinase-dependent serine phosphorylation of IRS-1 via suppression of Rac-1 activation. PEDF may play a protective role against hepatic insulin resistance in diabetes.