Regulation of hepatic gene expression and metabolism by FoxO proteins

项目摘要/摘要 肝脏过度产生葡萄糖在糖尿病的发展中起着核心作用。 糖尿病，胰岛素调节肝脏葡萄糖产生(HGP)的能力受损。 FOXO转录因子是胰岛素的主要靶标，在胰岛素调节中发挥重要作用 胰岛素对肝脏糖脂代谢的多方面影响，包括 糖异生、糖酵解和脂肪生成。然而，FoxO 蛋白质以一种综合的方式发挥这些不同的作用仍然知之甚少。 在我们之前的资助期间，我们发现a)FoxO蛋白也发挥着重要的作用 脂肪调节对肝内脂肪分解和脂肪酸氧化的影响 介导脂肪分解第一步的三酰甘油脂肪酶(ATGL)及其抑制物 G0/S1 Switch 2基因(G0S2)和b)ATGL依赖的脂解在介导 FoxO蛋白在肝脏中的不同作用，包括对糖异生、糖酵解和 生脂基因的表达和代谢。这些研究还表明，ATGL依赖 FoxO1对糖酵解和糖异生基因的影响需要脂解作用 表达，并计划在小鼠模型和分离的肝细胞中进行进一步的研究 更好地了解调节脂代谢和脂肪代谢之间这种新联系的具体机制 胰岛素/FoxO途径的血糖调节。 此外，使用肝脏特异性胰岛素受体(IR)基因敲除(LIRKO)和IR/FoxO1 对于双基因敲除(LIRFKO)小鼠，我们还发现破坏肝脏中的FoxO1就足够了 恢复胰岛素维持血糖稳态和抑制HGP的能力(基于 缺乏肝脏胰岛素受体的小鼠的正常血糖高胰岛素钳夹研究)。这些 结果表明：(A)FoxO1的抑制对直接(肝脏)和间接作用都是至关重要的 胰岛素对HGP和葡萄糖利用的影响，以及(B)胰岛素的肝外效应足以 当肝脏FoxO1活性降低时，维持正常的全身和肝脏葡萄糖代谢 打乱了。基于这些发现，利用转基因和基因敲除小鼠进行的其他研究 计划通过模型、细胞培养和胰岛素钳夹技术来确定ATGL- 依赖性脂解在FoxO1对肝脏葡萄糖的调节作用中也起着关键作用 肝胰岛素抵抗时的代谢及是否靶向ATGL及其受体 下游效应物可能为糖尿病的治疗提供有效的策略 肝脏胰岛素抵抗患者。

Project Summary/Abstract Excessive production of glucose by the liver plays a central role in the development of diabetes, where the ability of insulin to regulate hepatic glucose production (HGP) is impaired. FoxO transcription factors are major targets of insulin and play an important role in mediating effects of insulin on multiple aspects of glucose and lipid metabolism in the liver, including gluconeogenesis, glycolysis and lipogenesis. However, the mechanisms by which FoxO proteins exert these diverse effects in an integrated fashion remain poorly understood. During our previous funding period, we found that a) FoxO proteins also exert important effects on intrahepatic lipolysis and fatty acid oxidation via the regulation of adipose triacylglycerol lipase (ATGL), which mediates the first step in lipolysis, and its inhibitor, the G0/S1 switch 2 gene (G0S2), and b) ATGL-dependent lipolysis plays a critical role in mediating diverse effects of FoxO proteins in the liver, including effects on gluconeogenic, glycolytic and lipogenic gene expression and metabolism. These studies also indicate that ATGL-dependent lipolysis is required to mediate effects of FoxO1 on glycolytic and gluconeogenic gene expression, and additional studies are planned in mouse models and isolated hepatocytes to better understand specific mechanisms mediating this novel link between lipid metabolism and glucoregulation by the insulin/FoxO pathway. In addition, using liver-specific insulin receptor (IR) knockout (LIRKO) and IR/FoxO1 double knockout (LIRFKO) mice, we also found that disrupting FoxO1 in the liver was sufficient to restore the ability of insulin to maintain glucose homeostasis and suppress HGP (based on euglycemic hyperinsulinemic clamp studies) in mice lacking the hepatic insulin receptor. These results indicate that (a) inhibition of FoxO1 is critical for both direct (hepatic) and indirect effects of insulin on HGP and glucose utilization, and (b) extrahepatic effects of insulin are sufficient to maintain normal whole-body and hepatic glucose metabolism when liver FoxO1 activity is disrupted. Based on these findings, additional studies utilizing transgenic and knockout mouse models, cell culture and insulin clamp techniques are planned to determine whether ATGL- dependent lipolysis also plays a critical role in mediating effects of FoxO1 on hepatic glucose metabolism in the setting of hepatic insulin resistance, and whether targeting ATGL and its downstream effectors may provide an effective strategy for treatment of diabetes mellitus in patients with hepatic insulin resistance.