Hepatic insulin resistance integrates T2D and NAFLD

肝脏胰岛素抵抗整合了 T2D 和 NAFLD

• 批准号: 10792348
• 负责人: Morris F. White
• 金额: $ 15.05万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10792348
• 关键词: Acceleration; Activins; Adipose tissue; Adult; Albumins; Amendment; Animals; Attenuated; Award; Benign; Beverages; Cholesterol; Chronic; Clinical; Consumption; Data; Diabetes Mellitus; Diet; Disease Progression; Dyslipidemias; Economic Burden; Epidemic; Esterification; FOXO1A gene; Family; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Feedback; Fibrosis; Follistatin; Food; Fructose; GDF8 gene; Gene Expression; Genetic; Genetic Transcription; Glucose; Glucose Intolerance; Glycerol; Health; Hepatic; Hepatocyte; High Fat Diet; Human; Hyperinsulinism; Impairment; Inflammation; Inflammatory; Insulin; Insulin Receptor; Insulin Resistance; Ketohexokinase; Label; Leg; Life; Ligands; Link; Lipolysis; Liver; Liver Fibrosis; Mediating; Metabolic; Metabolic Diseases; Metabolism; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; PIK3CG gene; Pathway interactions; Patients; Peripheral; Persons; Phosphorylation; Phosphotransferases; Resistance; Risk Factors; Signal Transduction; Site; Source; Sucrose; TNF gene; Testing; Thinness; Tissues; Transcriptional Regulation; Transforming Growth Factor beta; Transgenic Mice; Triglycerides; Work; alpha-glycerophosphoric acid; blood glucose regulation; experimental study; feeding; fibroblast growth factor 21; glucose output; glucose production; insulin receptor substrate 1 protein; insulin secretion; insulin signaling; lipid biosynthesis; liver inflammation; liver metabolism; metabolomics; mouse genetics; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; recruit; saturated fat; sugar; western diet

This proposal investigates mechanisms that combine T2D (type 2 diabetes) with NAFLD (non-alcoholic fatty liver disease), which progress during chronic hepatic insulin resistance to life-threatening NASH (non-alcoholic steatohepatitis). Several studies argue that selective hepatic insulin resistance is required to integrate T2D with NAFLD/NASH. Regardless, we posit that complete hepatic insulin resistance exacerbates NAFLD/NASH and T2D in mice fed the western GAN diet—which models common sugar-sweetened food and beverages associated with T2D and NAFLD/NASH in patients. We model complete hepatic insulin resistance with ‘LDKO’ mice that lack hepatic Irs1 (insulin receptor substrate 1) and Irs2, which activates FoxO1 mediated transcription to induce hepatic Fst (follistatin) expression and secretion. Circulating hepatic Fst causes WAT (white adipose tissue) insulin resistance and uncontrolled lipolysis. Circulating FST in human NAFLD patients correlates with insulin resistance in leg fat to release fatty acids from this benign storage site. Our proposal investigates whether hepatic FoxO1 and Fst promote the progression of NAFLD to NASH during hepatic insulin resistance. We use mouse genetics to determine whether inactivation of FoxO1 or Fst in LDKO mice fed the GAN diet can attenuate both NAFLD/NASH trajectory and liver inflammatory gene expression to identify pathways promoting NAFLD and its progression to NASH during hepatic insulin resistance. We test this hypothesis by inactivating TNFα in LDKO mice fed the GAN diet. A simpler high-fructose diet (HFruD60%) is used to investigate whether FoxO1 and Fst promote NAFLD/NASH from hepatic fructose metabolism. Re- esterification of circulating fatty acids with hepatic Gro3P (glycerol-3-phosphate)—a fructose metabolite—is a major source of hepatic triacylglycerol in NAFLD patients. To understand whether fructose promotes NAFLD/NASH by re-esterification of circulating fatty acid during complete hepatic insulin resistance, we can investigate LDKO mice fed the HFruD60% without or after deletion of hepatic FoxO1 or Fst—or Khk (Ketohexokinase) that is essential for hepatic metabolism of fructose. Feeding mice [13C]fructose enables LC- MS to determine the incorporation of fructose metabolites into the glycerol or fatty acid moieties of liver or circulating triacylglycerol. In humans and mice, NAFLD might arise from ‘selective insulin resistance’—owing to uncontrolled hepatic glucose output in conjunction with some insulin-stimulated lipogenesis; however, we posit that selective hepatic insulin resistance might have the opposite effect and attenuate NAFLD/NASH owing to inhibition of FoxO1 and Fst. Since chronic nutrient excess can suppress hepatic Irs2, we investigate GAN diet- induced NAFLD/NASH and T2D in mice lacking hepatic Irs2 (LKO2 mice) or Irs1 (LKO1 mice), as well as our novel transgenic mice expressing nutrient-insensitive Irs2tg in hepatocytes. Completion of our proposal can impact human health by identifying systemic and hepatic metabolic regulatory mechanisms by which hepatic insulin resistance integrates T2D with NAFLD/NASH.

该提案调查了将T2D（2型糖尿病）与NAFLD（非酒精脂肪的糖尿病）相结合的机制 肝病），在慢性肝胰岛素抵抗威胁生命NASH期间的进展（非酒精 脂肪性肝炎）。几项研究认为，需要选择性肝胰岛素抵抗才能将T2D与 nafld/nash。无论如何，我们的位置使肝胰岛素抵抗完全加剧了NAFLD/NASH和 T2D喂食西甘饮食的小鼠 - 造型常见的糖甜食物和卧室 与患者的T2D和NAFLD/NASH相关。我们用“ ldko”对完成肝胰岛素耐药性建模 缺乏肝素IRS1（胰岛素受体底物1）和IRS2的小鼠，它激活FOXO1介导 转录以诱导肝FST（Follistatin）表达和分泌。循环肝FST会导致WAT （白色脂肪组织）胰岛素抵抗和不受控制的脂解。在人类NAFLD患者中循环FST 与腿部脂肪中的胰岛素耐药性相关，以从该良性存储部位释放脂肪酸。我们的建议 调查Hepatitic FoxO1和FST是否在肝脏期间促进NAFLD向NASS的发展 胰岛素抵抗。我们使用小鼠遗传学来确定LDKO小鼠中FOXO1或FST的失活 喂养饮食可以减弱NAFLD/NASH轨迹和肝脏炎症基因表达 确定促进NAFLD及其在肝胰岛素抵抗期间向NASH的进展的途径。我们测试 通过在LDKO小鼠中灭活TNFα的假设，喂养了GAN饮食。更简单的高果糖饮食（Hfrud60％）是 用于研究FOXO1和FST是否促进肝果糖代谢中的NAFLD/NASH。关于- 用肝GRO3P（甘油-3-磷酸）（一种果糖代谢物）酯化循环脂肪酸的酯化 NAFLD患者中肝三酰基甘油的主要来源。了解果糖是否促进 NAFLD/NASH通过在完全肝胰岛素抵抗期间重新溶解循环脂肪酸，我们可以 调查hfrud60％的ldko小鼠，没有肝脏foxo1或fst的删除或khk （Ketohexokinase）对于果糖的肝脏代谢至关重要。喂养小鼠[13C]果糖使LC- MS确定将果糖代谢物掺入肝脏或脂肪酸部分中的肝脏或 循环三酰基甘油。在人类和老鼠中，NAFLD可能源于“选择性胰岛素抵抗”，因此 不受控制的肝葡萄糖输出与某些胰岛素刺激的脂肪形成结合；但是，我们定位 选择性的肝胰岛素抵抗可能具有相反的效果，并且由于 抑制FOXO1和FST。由于慢性营养过量会抑制肝IRS2，因此我们研究了gan饮食 - 在缺乏肝IRS2（LKO2小鼠）或IRS1（LKO1小鼠）的小鼠中诱导NAFLD/NASH和T2D，以及我们 在肝细胞中表达营养不敏感IRS2TG的新型转基因小鼠。完成我们的建议可以 通过识别肝的系统性和肝脏代谢调节机制来影响人类健康 胰岛素抵抗将T2D与NAFLD/NASH整合。