Regulation of hepatic gene expression and metabolism by FoxO proteins

FoxO蛋白对肝基因表达和代谢的调节

• 批准号: 10319487
• 负责人: Terry G. Unterman
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319487
• 关键词: Acetyl Coenzyme A; Acetylation; Adipose tissue; Cell Culture Techniques; Closure by clamp; Complex; Deacetylation; Development; Diabetes Mellitus; Extrahepatic; FOXO1A gene; Fatty Acids; Funding; Gene Expression; Genes; Glucokinase; Gluconeogenesis; Glucose; Glucose Intolerance; Glycolysis; Goals; HDAC3 gene; Hepatic; Hepatocyte; Histone Deacetylase; Impairment; Incidence; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Like Growth-Factor Binding Protein 1; Knock-out; Knockout Mice; Laboratories; Lead; Link; Lipase; Lipolysis; Liver; Mediating; Metabolism; Morbidity - disease rate; Mus; NADH; Nuclear Proteins; Pathway interactions; Patients; Phosphoenolpyruvate Carboxylase; Phosphorylation; Planning Techniques; Play; Prevention; Prevention strategy; Protein Acetylation; Protein-Serine-Threonine Kinases; Proteins; Regulation; Reporting; Role; SIRT1 gene; Serine; Signal Transduction; Sirtuins; Source; Transgenic Mice; Veterans; base; blood glucose regulation; diabetes pathogenesis; fatty acid metabolism; fatty acid oxidation; forkhead protein; glucose metabolism; glucose production; glucose tolerance; improved; inhibitor/antagonist; insight; intrahepatic; knock-down; lipid biosynthesis; lipid metabolism; military veteran; mortality; mouse model; novel; protein metabolism; transcription factor; treatment strategy

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.

项目摘要/摘要 肝脏过度产生葡萄糖在发展中起着核心作用 糖尿病，胰岛素调节肝葡萄糖产生（HGP）的能力受到损害。 FOXO转录因子是胰岛素的主要靶标，并且在介导中起重要作用 胰岛素对肝脏葡萄糖和脂质代谢的多个方面的影响，包括 糖异生，糖酵解和脂肪生成。但是，Foxo的机制 蛋白质以综合方式施加这些多样化的效果仍然知之甚少。 在以前的资金期间，我们发现a）foxo蛋白也发挥重要作用 通过调节脂肪对肝内脂解和脂肪酸氧化的影响 介导脂解的第一步及其抑制剂的三酰基甘油脂肪酶（ATGL）， G0/S1开关2基因（G0S2），b）依赖ATGL的脂解在介导中起着至关重要的作用 FOXO蛋白在肝脏中的不同作用，包括对糖原，糖酵解和 脂肪生成基因表达和代谢。这些研究还表明ATGL依赖性 需要脂解来介导FOXO1对糖酵解和糖糖原性基因的影响 在小鼠模型和孤立的肝细胞中计划进行表达，并计划进行其他研究 更好地了解介导脂质代谢与 胰岛素/FOXO途径的葡萄糖调节。 另外，使用肝特异性胰岛素受体（IR）敲除（LIRKO）和IR/FOXO1 双重敲除（lirfko）小鼠，我们还发现肝脏中的FOXO1就足够了 恢复胰岛素维持葡萄糖稳态和抑制HGP的能力（基于 在缺乏肝胰岛素受体的小鼠中，葡萄糖高胰岛素夹研究）。这些 结果表明（a）抑制FOXO1对于直接（肝）和间接影响至关重要 HGP和葡萄糖利用率上的胰岛素的胰岛素，（b）胰岛素的肝外作用足以使 当肝脏FOXO1活性是正常的全身和肝葡萄糖代谢 破坏了。基于这些发现，利用转基因和基因敲除小鼠的其他研究 计划制定模型，细胞培养和胰岛素夹技术，以确定ATGL-是否是否 依赖性脂肪解析在介导FOXO1对肝葡萄糖的介导作用中也起着至关重要的作用 在肝胰岛素抵抗环境中的代谢，以及是否针对ATGL及其 下游效应子可以提供有效的策略来治疗糖尿病 具有肝胰岛素抵抗的患者。