Prolonged treatment of primary Hepatocytes with oleate induces insulin resistance through p38 mitogen-activated protein kinase
Prolonged treatment of primary Hepatocytes with oleate induces insulin resistance through p38 mitogen-activated protein kinase
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DOI：
10.1074/jbc.m609701200
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发表时间：
2007-05-11
影响因子：
4.8
通讯作者：
Cao, Wenhong
中科院分区：
文献类型：
--
作者：
Liu, Hui-Yu;Collins, Qu Fan;Cao, Wenhong
游离脂肪酸（FFA）被认为是肥胖与II型糖尿病之间的主要环境因素。我们最近报道FFA可以通过p38丝裂原活化蛋白激酶（p38）诱导肝细胞凋亡。在这项研究中，我们研究了p38在油酸诱导的肝脏胰岛素抵抗中的作用。我们的研究结果表明，油酸酯的原代肝细胞的长期治疗钝化胰岛素抑制肝细胞新生，并减少胰岛素诱导的磷酸化Akt的p38依赖的方式。油酸酯减少胰岛素诱导的Akt磷酸化与p38的激活相关。在存在p38抑制的情况下，肝细胞长时间暴露于油酸未能降低胰岛素刺激的Akt磷酸化。针对p38 α的siRNA阻止油酸对胰岛素诱导的Akt磷酸化的抑制。此外，肝细胞长时间暴露于油酸降低胰岛素诱导的IRS 1/2酪氨酸磷酸化，而轻微增加IRS的丝氨酸磷酸化。油酸对胰岛素刺激的肝细胞IRS 1/2酪氨酸磷酸化的抑制作用可被p38的抑制所逆转。我们进一步表明，原代肝细胞长时间暴露于油酸升高的蛋白水平的磷酸酶和张力蛋白同源物10号染色体上删除（PTEN）基因的p38依赖性的方式，但没有影响的mRNA水平的PTEN。敲低PTEN基因阻止油酸抑制Akt的胰岛素活化和胰岛素抑制胰岛β细胞生成。总之，这项研究的结果表明，p38在油酸诱导的肝脏胰岛素抵抗中起着关键作用。
Free fatty acid (FFA) is believed to be a major environmental factor linking obesity to Type II diabetes. We have recently reported that FFA can induce gluconeogenesis in hepatocytes through p38 mitogen-activated protein kinase (p38). In this study, we have investigated the role of p38 in oleate-induced hepatic insulin resistance. Our results show that a prolonged treatment of primary hepatocytes with oleate blunted insulin suppression of hepatic gluconeogenesis, and decreased insulin-induced phosphorylation of Akt in a p38-dependent manner. Reduction of the insulin-induced Akt phosphorylation by oleate correlated with activation of p38. In the presence of p38 inhibition, prolonged exposure of hepatocytes to oleate failed to reduce insulin-stimulated phosphorylation of Akt. An siRNA against p38 alpha prevented oleate suppression of the insulin-induced phosphorylation of Akt. Furthermore, a prolonged exposure of hepatocytes to oleate decreased insulin-induced tyrosine phosphorylation of IRS1/2, while slightly increasing serine phosphorylation of IRS. The decrease of insulin-stimulated tyrosine phosphorylation of IRS1/2 in hepatocytes by oleate was reversed by the inhibition of p38. We further show that a prolonged exposure of primary hepatocytes to oleate elevated the protein level of the phosphatase and tensin homolog deleted on chromosome 10 ( PTEN) gene in a p38-dependent manner, but had no effect on the mRNA level of PTEN. Knocking down the PTEN gene prevented oleate to inhibit insulin activation of Akt and insulin suppression of gluconeogenesis. Together, results from this study demonstrate a critical role for p38 in oleate-induced hepatic insulin resistance.