Peroxisome proliferator-activated receptorβ/δ activation is essential for modulating p-Foxo1/Foxo1 status in functional insulin-positive cell differentiation.
Peroxisome proliferator-activated receptorβ/δ activation is essential for modulating p-Foxo1/Foxo1 status in functional insulin-positive cell differentiation.
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DOI：
10.1038/cddis.2015.88
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发表时间：
2015-04-09
影响因子：
9
通讯作者：
Lou Y
中科院分区：
文献类型：
--
作者：
Li L;Li T;Zhang Y;Pan Z;Wu B;Huang X;Zhang Y;Mei Y;Ge L;Shen G;Ge RS;Zhu D;Lou Y
过氧化物酶体增殖物激活受体（PPAR）参与能量稳态，并通过其对非胰腺组织的影响在糖尿病治疗中发挥重要作用。病理微环境可能影响维持干细胞分化的代谢需求。因此，了解 PPAR 对胰腺 β 细胞分化的机制可能有助于找到胰腺疾病条件下能量稳态破坏的潜在靶点。 PPARs 通过线粒体氧化磷酸化参与干细胞分化，但功能性胰岛素阳性 (INS+) 细胞分化中亚型成员的激活和下游调节仍不清楚。在这里，我们展示了 PPARβ/δ 激活在决定 INS+ 细胞分化和功能成熟中的新作用。我们发现在体内和体外，小鼠胚胎胰腺或胰腺成熟阶段的干细胞衍生的 INS+ 细胞中 PPARβ/δ 表达选择性上调。引人注目的是，鉴于体外生成 INS+ 细胞的效率低下，PPARβ/δ 激活显示小鼠和人类 ES 细胞衍生的 INS+ 细胞数量和胰岛素分泌增加。这种现象与叉头盒蛋白 O1 (Foxo1) 核穿梭密切相关，其核穿梭依赖于 PPARβ/δ 下游 PI3K/Akt 信号转导。本研究揭示了 PPARβ/δ 激活对 p-Foxo1/Foxo1 状态的重要作用，进而通过影响胰腺和十二指肠同源盒-1 表达来决定 INS+ 细胞的生成和胰岛素分泌。结果证明了 PPARβ/δ 激活促进功能性 INS+ 细胞分化的潜在机制。它还为抗糖尿病药物的发现和人类细胞疗法的临床应用提供了潜在的靶点。
Peroxisome proliferator-activated receptors (PPARs) participate in energy homeostasis and play essential roles in diabetes therapy through their effects on non-pancreas tissues. Pathological microenvironment may influence the metabolic requirements for the maintenance of stem cell differentiation. Accordingly, understanding the mechanisms of PPARs on pancreatic β-cell differentiation may be helpful to find the underlying targets of disrupted energy homeostasis under the pancreatic disease condition. PPARs are involved in stem cell differentiation via mitochondrial oxidative phosphorylation, but the subtype member activation and the downstream regulation in functional insulin-positive (INS+) cell differentiation remain unclear. Here, we show a novel role of PPARβ/δ activation in determining INS+ cell differentiation and functional maturation. We found PPARβ/δ expression selectively upregulated in mouse embryonic pancreases or stem cells-derived INS+ cells at the pancreatic mature stage in vivo and in vitro. Strikingly, given the inefficiency of generating INS+ cells in vitro, PPARβ/δ activation displayed increasing mouse and human ES cell-derived INS+ cell numbers and insulin secretion. This phenomenon was closely associated with the forkhead box protein O1 (Foxo1) nuclear shuttling, which was dependent on PPARβ/δ downstream PI3K/Akt signaling transduction. The present study reveals the essential role of PPARβ/δ activation on p-Foxo1/Foxo1 status, and in turn, determining INS+ cell generation and insulin secretion via affecting pancreatic and duodenal homeobox-1 expression. The results demonstrate the underlying mechanism by which PPARβ/δ activation promotes functional INS+ cell differentiation. It also provides potential targets for anti-diabetes drug discovery and hopeful clinical applications in human cell therapy.