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.

这项建议调查了T2D(2型糖尿病)和NAFLD(非酒精性脂肪)结合的机制 肝脏疾病)，在慢性肝脏胰岛素抵抗危及生命的NASH(非酒精性)期间进展 脂肪性肝炎)。几项研究认为，选择性肝脏胰岛素抵抗是T2D和T2D整合的必要条件 NAFLD/NASH。无论如何，我们假设完全的肝脏胰岛素抵抗会加重NAFLD/NASH和 喂食西方甘氨酸饮食的小鼠的T2D-模拟常见的含糖食物和饮料 与T2D和NAFLD/NASH相关。我们用‘LDKO’来模拟完全的肝脏胰岛素抵抗 缺乏肝脏IRS1(胰岛素受体底物1)和IRS2的小鼠，IRS2激活FoxO1介导的 转录诱导肝脏Fst(卵泡抑素)的表达和分泌。循环肝脂致水 (白色脂肪组织)胰岛素抵抗和不受控制的脂肪分解。非酒精性脂肪肝患者循环FST的研究 与腿部脂肪中的胰岛素抵抗相关，从而从这个良性的储存部位释放脂肪酸。我们的建议 探讨肝脏FoxO1和Fst是否促进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FoxO1或Fst是否失活 饲喂GaN饮食可减轻NAFLD/NASH轨迹和肝脏炎症基因表达 确定在肝脏胰岛素抵抗期间促进NAFLD及其进展为NASH的途径。我们测试 这一假说是通过灭活喂食GaN饮食的LDKO小鼠的肿瘤坏死因子α来实现的。更简单的高果糖饮食(HFruD60%)是 用来研究FoxO1和Fst是否从肝脏果糖代谢促进NAFLD/NASH。重新- 循环脂肪酸与肝脏Gro3P(3-磷酸甘油)-一种果糖代谢物-的酯化反应是一种 NAFLD患者肝脏三酰甘油的主要来源。要了解果糖是否能促进 NAFLD/NASH在完全肝脏胰岛素抵抗期间通过循环脂肪酸的再酯化，我们可以 肝FoxO1、Fst-或KHK缺失前后饲喂HFruD60%的LDKO小鼠的研究 (酮己糖)，对肝脏果糖代谢是必需的。喂饲小鼠[13C]果糖可使LC- MS以确定将果糖代谢物掺入肝脏的甘油或脂肪酸部分或 循环中的三酰甘油。在人类和小鼠中，非酒精性脂肪肝可能源于“选择性胰岛素抵抗”--由于 不受控制的肝脏葡萄糖输出与一些胰岛素刺激的脂肪生成有关；然而，我们假设 选择性肝脏胰岛素抵抗可能具有相反的作用，并减轻NAFLD/NASH FoxO1和Fst的抑制作用。由于慢性营养过剩会抑制肝脏Irs2，我们研究了GaN饮食- 在缺乏肝脏IRS2(LKO2小鼠)或IRS1(LKO1小鼠)的小鼠以及我们的 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 通过确定全身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结合起来。