Erythropoietin alleviates hepatic insulin resistance via PPARγ-dependent AKT activation.
Erythropoietin alleviates hepatic insulin resistance via PPARγ-dependent AKT activation.
复制标题
促红细胞生成素通过 PPAR γ 依赖性 AKT 激活减轻肝脏胰岛素抵抗
DOI：
10.1038/srep17878
复制
发表时间：
2015-12-08
影响因子：
4.6
通讯作者：
Zhu D
中科院分区：
文献类型：
--
作者：
Ge Z;Zhang P;Hong T;Tang S;Meng R;Bi Y;Zhu D
促红细胞生成素(EPO)对糖代谢和胰岛素抵抗有良好的作用。然而，这些效应背后的机制尚未阐明。本研究旨在探讨促红细胞生成素对肝脏葡萄糖代谢的影响。在这里，我们报道了EPO促进了棕榈酸(PA)处理的HepG2细胞和高脂饮食(HFD)喂养的小鼠肝脏中磷脂酰肌醇3-激酶(PI3K)/AKT通路的激活，而腺病毒介导的EPO介导的促红细胞生成素受体(EPOR)沉默则阻断了EPO诱导的HepG2细胞中的AKT信号。重要的是，过氧化物酶体增殖物激活受体γ(PPARγ)拮抗剂和PPARγ小干扰RNA(SiRNA)可抑制EPO诱导的p-AKT增加。慢病毒载体介导的肝脏PPARγ沉默抑制促红细胞生成素介导的糖耐量增加、胰岛素敏感性和肝脏AKT激活。此外，EPO激活了AMPK/sirtuin1信号通路，AMPKα和SIRT1基因敲除分别减弱了EPO诱导的PPARγ表达和去乙酰化以及依赖于PPARγ的AKT激活。综上所述，这些发现提示PPARγ参与了EPO/EpoR诱导的AKT激活，通过EPO靶向PPARγ/AKT通路可能对肝脏胰岛素抵抗和2型糖尿病有治疗意义。
Erythropoietin (EPO) has beneficial effects on glucose metabolism and insulin resistance. However, the mechanism underlying these effects has not yet been elucidated. This study aimed to investigate how EPO affects hepatic glucose metabolism. Here, we report that EPO administration promoted phosphatidylinositol 3-kinase (PI3K)/AKT pathway activation in palmitic acid (PA)-treated HepG2 cells and in the liver of high-fat diet (HFD)-fed mice, whereas adenovirus-mediated silencing of the erythropoietin receptor (EPOR) blocked EPO-induced AKT signalling in HepG2 cells. Importantly, a peroxisome proliferator-activated receptor γ (PPARγ) antagonist and PPARγ small interfering RNA (siRNA) abrogated the EPO-induced increase in p-AKT in HepG2 cells. Lentiviral vector-mediated hepatic PPARγ silencing in HFD-fed C57BL/6 mice impaired EPO-mediated increases in glucose tolerance, insulin sensitivity and hepatic AKT activation. Furthermore, EPO activated the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) signalling pathway, and AMPKα and SIRT1 knockdown each attenuated the EPO-induced PPARγ expression and deacetylation and PPARγ-dependent AKT activation in HepG2 cells. In summary, these findings suggest that PPARγ is involved in EPO/EPOR-induced AKT activation, and targeting the PPARγ/AKT pathway via EPO may have therapeutic implications for hepatic insulin resistance and type 2 diabetes.