Metabolic Crosstalk During Hepatic Insulin Resistance

肝脏胰岛素抵抗期间的代谢串扰

• 批准号: 9749986
• 负责人: Morris F. White
• 金额: $ 53.32万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9749986
• 关键词: Adipose tissue; Alleles; Attenuated; Brown Fat; Communication; Cyclic AMP-Dependent Protein Kinases; Data; Dependovirus; Development; Diabetes Mellitus; Disease; Dyslipidemias; Expression Profiling; Extrahepatic; FOXO1A gene; Fatty Liver; Female; Follistatin; Funding; Gene Expression; Genes; Genetic; Glucose Intolerance; Goals; Growth; Hepatic; Hepatocyte; Homeostasis; Hyperglycemia; Hyperinsulinism; IRS1 gene; IRS2 gene; Insulin; Insulin Receptor; Insulin Resistance; Life; Link; Lipids; Lipolysis; Liver; Liver Mitochondria; Liver diseases; LoxP-flanked allele; Mediating; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Mitochondria; Modeling; Molecular; Mus; Muscle; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Pathway interactions; Peripheral; Permeability; Phosphorylation; Phosphotransferases; Primary carcinoma of the liver cells; Protein Dephosphorylation; Proteins; Publishing; Regulation; Resistance; Role; Signal Pathway; Site; Skeletal Muscle; Tissues; Work; autocrine; base; cardiovascular disorder risk; cyclophilin D; fibroblast growth factor 21; glucose production; glucose tolerance; improved; innovation; insulin receptor substrate 1 protein; insulin sensitivity; insulin signaling; knock-down; liver metabolism; male; mitochondrial dysfunction; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; overexpression; screening; transcription factor

Type 2 diabetes (T2DM) is a life-threatening disease characterized by hepatic and peripheral insulin resistance, which dysregulate inter-tissue metabolic flux and communication to promote hyperglycemia and dyslipidemia. Insulin signaling throughout the body is mediated by the insulin receptor substrate proteins IRS1 and IRS2. Within the liver, insulin regulates gene expression and metabolism largely via the IRS-dependent inhibition of transcription factor FoxO1. This renewal is founded on the striking observation that hepatic insulin resistance in ‘LDKO’ mice—which lack Irs1 and Irs2 in liver—propagates insulin resistance to the skeletal muscle and white and brown adipose tissues (WAT and BAT). Excessive hepatic glucose production (HGP) during diabetes owes, at least in part, to hepatic insulin resistance and activation of gluconeogenic genes by FoxO1. However, HGP is normalized in LDKO-mice upon inactivation/deletion of hepatic FoxO1 (i.e., ‘LTKO’ mice), suggesting that unknown, FoxO1-dependent factors secreted by the liver (‘hepatokines’) act to promote insulin resistance in peripheral tissues. This competitive renewal focuses upon the dysregulated hepatokines in LDKO liver to reveal how peripheral metabolic disease depends upon FoxO1—rather than hepatic insulin signaling per se. This is an innovative departure from the study of a single tissue or pathway that can, moreover, reveal the mechanisms by which hepatic resistance alone gives rise to many of the features of T2DM in mice. Robust preliminary data allow us to focus upon functionally important hepatokines that are elevated or decreased in LDKO liver, but normalized in LTKO liver. In addition to increased cardiovascular disease risk, T2DM is associated with non-alcoholic fatty liver disease (NAFLD) that can progress to non-alcoholic steatohepatitis (NASH) and eventual hepatocellular carcinoma (HCC); we have further established that this progression is attenuated in LTKO mice. Using deletion of floxed hepatokine alleles—or hepatotropic AAV (adeno-associated virus) to knock-down or over-express hepatokine genes—we employ both LDKO and LTKO mice to reveal (and corroborate) the effects of dysregulated FoxO1-dependent hepatokines upon systemic nutrient homeostasis and the progression of liver disease.

2 型糖尿病 (T2DM) 是一种危及生命的疾病，其特征是肝脏和外周胰岛素抵抗，组织间代谢通量和通讯失调，从而促进高血糖和血脂异常，体内胰岛素信号传导由胰岛素受体底物蛋白 IRS1 和 IRS1 介导。 IRS2。在肝脏内，胰岛素主要通过 IRS 依赖性转录因子 FoxO1 的抑制来调节基因表达和代谢。这种更新是基于肝脏胰岛素抵抗的惊人观察。肝脏中缺乏 Irs1 和 Irs2 的“LDKO”小鼠将胰岛素抵抗传播到骨骼肌以及白色和棕色脂肪组织（WAT 和 BAT），糖尿病期间肝脏葡萄糖产生过多（HGP）至少部分归因于肝脏。 FoxO1 的胰岛素抵抗和糖异生基因激活 然而，在肝 FoxO1 失活/删除后，HGP 在 LDKO 小鼠中正常化。 （即“LTKO”小鼠），表明肝脏分泌的未知的 FoxO1 依赖性因子（“肝因子”）可促进外周组织中的胰岛素抵抗，这种竞争性更新的重点是 LDKO 肝脏中失调的肝因子，以揭示外周组织如何产生胰岛素抵抗。代谢疾病依赖于 FoxO1，而不是肝脏胰岛素信号传导本身，这是对单一组织或途径的研究的创新，而且可以揭示单独肝抵抗引起的机制。小鼠 T2DM 的许多特征使我们能够关注功能上重要的肝因子，这些因子在 LDKO 肝脏中升高或降低，但在 LTKO 肝脏中正常化。除了心血管疾病风险增加之外，T2DM 还与非酒精相关。脂肪肝病 (NAFLD) 可进展为非酒精性脂肪性肝炎 (NASH) 并最终发展为肝细胞癌 (HCC)；我们进一步确定，这种进展是通过删除 floxed 肝因子等位基因或亲肝 AAV（腺相关病毒）来敲低或过度表达肝因子基因，我们使用 LDKO 和 LTKO 小鼠来揭示（并证实）失调的 FoxO1 的影响。依赖于全身营养稳态和肝病进展的肝因子。