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.

该提案研究了联合收割机T2 D（2型糖尿病）与NAFLD（非酒精性脂肪肝）相结合的机制。 肝脏疾病），其在慢性肝脏胰岛素抵抗期间进展为危及生命的NASH（非酒精性 脂肪性肝炎）。几项研究认为，选择性肝胰岛素抵抗是整合T2 D与 NAFLD/NASH。无论如何，我们认为完全的肝脏胰岛素抵抗会加重NAFLD/NASH， 喂食西方GAN饮食的小鼠中的T2 D-其模拟常见的含糖食物和饮料 与T2 D和NAFLD/NASH相关。我们用“LDKO”模拟完全肝胰岛素抵抗 缺乏肝脏Irs 1（胰岛素受体底物1）和Irs 2（激活FoxO 1介导的 转录以诱导肝Fst（卵泡抑素）表达和分泌。循环肝Fst导致WAT （白色脂肪组织）胰岛素抵抗和不受控制的脂解。人类NAFLD患者的循环FST 与腿部脂肪中的胰岛素抵抗相关，以从这个良性储存部位释放脂肪酸。我们的建议 研究肝脏FoxO 1和Fst是否促进肝脏中NAFLD向NASH的进展， 胰岛素抵抗我们使用小鼠遗传学来确定LDKO小鼠中FoxO 1或Fst的失活是否 喂食GAN饮食可以减弱NAFLD/NASH轨迹和肝脏炎症基因表达， 确定在肝胰岛素抵抗期间促进NAFLD及其进展为NASH的途径。我们测试 通过灭活喂食GAN饮食的LDKO小鼠中的TNFα证实了这一假设。一个简单的高果糖饮食（HFruD 60%）是 用于研究FoxO 1和Fst是否促进来自肝脏果糖代谢的NAFLD/NASH。再- 循环脂肪酸与肝Gro 3 P（甘油-3-磷酸）-果糖代谢物-的酯化作用是一种 是NAFLD患者肝脏三酰甘油的主要来源。为了了解果糖是否能促进 通过在完全肝胰岛素抵抗期间循环脂肪酸的再酯化，我们可以 研究喂食HFruD 60%而不含或缺失肝脏FoxO 1或Fst-或Khk后的LDKO小鼠 （己酮糖激酶），其对于果糖的肝代谢是必需的。喂食小鼠[13 C]果糖可使LC- MS测定果糖代谢产物掺入肝脏的甘油或脂肪酸部分，或 循环甘油三酯。在人类和小鼠中，NAFLD可能是由“选择性胰岛素抵抗”引起的， 不受控制的肝葡萄糖输出与一些胰岛素刺激的脂肪生成有关;然而，我们认为， 由于选择性肝脏胰岛素抵抗可能会产生相反的作用并减轻NAFLD/NASH， 抑制FoxO 1和Fst.由于慢性营养过剩可以抑制肝脏Irs 2，我们研究了GAN饮食- 在缺乏肝脏Irs 2（LKO 2小鼠）或Irs 1（LKO 1小鼠）的小鼠中诱导NAFLD/NASH和T2 D，以及我们的 在肝细胞中表达营养不敏感的Irs 2 tg的新型转基因小鼠。完成我们的提案可以 通过识别系统和肝脏代谢调节机制来影响人类健康， 胰岛素抵抗整合了T2 D与NAFLD/NASH。