Hepatic deficiency of Poldip2 in type 2 diabetes modulates lipid and glucose homeostasis
Hepatic deficiency of Poldip2 in type 2 diabetes modulates lipid and glucose homeostasis
复制标题
2 型糖尿病患者肝脏缺乏 Poldip2 会抑制脂质和葡萄糖稳态
DOI：
10.1016/j.metabol.2019.153948
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发表时间：
2019-10-01
影响因子：
9.8
通讯作者：
Chen, Keyang
中科院分区：
文献类型：
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作者：
Jiang, Zhengxuan;Zhou, Jielin;Chen, Keyang
中度或低水平过氧化氢已被证明在血管平滑肌细胞（VSMC）功能中发挥重要作用，其中聚合酶dna定向相互作用蛋白2 （Poldip2）是NOX4活性的关键调节因子。在目前的研究中，我们意外地发现2型糖尿病（T2DM）显著抑制肝脏Poldip2的表达，而Poldip2的肝缺乏可能与肝脏胆固醇和血浆甘油三酯的失调有关。在培养的肝细胞中，我们发现胰岛素和瘦素在高葡萄糖浓度下都可以抑制肝脏中Poldip2的表达，但在正常血糖状态下，这种抑制作用完全被消除。在正常血糖状态下，敲低POLDIP2 siRNA显著损害胰岛素或瘦素诱导的H2O2，促进培养的肝细胞中胆固醇的积累。在体内恢复T2DM小鼠肝脏Poldip2的表达，与对照组相比，显著地恢复了肝脏中H2O2的生成，导致肝脏胆固醇积累和血浆甘油三酯水平显著改善。重要的是，肝脏中H2O2的适度诱导通过抑制PTEN和PTP1B活性显著改善肝脏PI3K-C-1/AKT信号或抑制PI3K-C-2 γ /AKT信号，从而抑制肝脏中HMGCR和SREBP2的胆固醇合成表达。此外，恢复糖尿病小鼠肝脏Poldip2表达可显著降低vldl -胆固醇生成速率，并显著抑制葡萄糖异生的PEPCK和G6Pase表达，从而显著改善糖尿病小鼠血浆胰岛素和葡萄糖水平，改善ITT和GTT结局。我们的研究结果表明，肝脏中Poldip2的失调可能导致糖尿病性血脂异常和高血糖。(C) 2019 Elsevier Inc.版权所有。
Moderate or low level hydrogen peroxides has been shown to play an important role in vascular smooth muscle cell (VSMC) function, in which the polymerase DNA-directed interacting protein 2 (Poldip2), functioned as a key regulator of NOX4 activity.In current study, we unexpectedly found that type 2 diabetes mellitus (T2DM) substantially suppresses the hepatic Poldip2 expression, and that the hepatic deficiency of Poldip2 may be correlated with dysregulation of hepatic cholesterol and plasma triglycerides. In cultured hepatocytes, we found that both insulin and leptin may inhibit hepatic expression of Poldip2 under high glucose concentration, but these suppressions were totally abolished under normoglycemic condition. POLDIP2 siRNA knockdown significantly impaired the H2O2 induction by insulin or leptin under normoglycemic condition, contributing the accumulation of cholesterol in cultured liver cells. The in vivo restoration of hepatic Poldip2 expression in T2DM mice remarkably rescued the moderate H2O2 generation in livers versus control mice, resulting in significant amelioration of hepatic cholesterol accumulation and plasma triglyceride levels. Importantly, the moderate induction of H2O2 in livers dramatically improved the hepatic PI3K-C-1/AKT signaling or dampened PI3K-C-2 gamma/AKT signaling through suppression of PTEN and PTP1B activities, thereby inhibiting the hepatic expression of HMGCR and SREBP2 for cholesterol synthesis. Moreover, the restitution of hepatic Poldip2 expression in diabetic mice significantly lowered the VLDL-cholesterol production rate, and substantially suppressed PEPCK and G6Pase expressions for gluconeogenesis, thus significantly improving the plasma insulin and glucose levels, and ITT and GTT outcomes in diabetic mice. Our findings suggest that hepatic dysregulation of Poldip2 may contribute to diabetic dyslipidemia and hyperglycemia. (C) 2019 Elsevier Inc. All rights reserved.