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 T2D（2 型糖尿病）与 NAFLD（非酒精性脂肪肝）相结合的机制。 肝病），在慢性肝胰岛素抵抗过程中进展为危及生命的 NASH（非酒精性脂肪肝） 多项研究认为，选择性肝胰岛素抵抗是 T2D 与 无论如何，我们认为完全的肝脏胰岛素抵抗会加重 NAFLD/NASH，并且 喂食西方 GAN 饮食（模拟常见含糖食品和饮料）的小鼠出现 T2D 我们用“LDKO”模拟了与 T2D 和 NAFLD/NASH 相关的完全肝胰岛素抵抗。 缺乏肝脏 Irs1（胰岛素受体底物 1）和 Irs2（可激活 FoxO1 介导的 Irs2）的小鼠 转录诱导肝 Fst（卵泡抑素）表达和分泌。循环肝 Fst 导致 WAT。 （白色脂肪组织）人类 NAFLD 患者的胰岛素抵抗和不受控制的脂肪分解。 与腿部脂肪中的胰岛素抵抗相关，从而从这个良性储存部位释放脂肪酸。 研究肝脏 FoxO1 和 Fst 是否促进 NAFLD 进展为 NASH 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 饮食可以减弱 NAFLD/NASH 轨迹和肝脏炎症基因表达， 我们测试了肝脏胰岛素抵抗期间促进 NAFLD 及其进展为 NASH 的途径。 这一假设是通过在喂食 GAN 饮食的 LDKO 小鼠中灭活 TNFα 来实现的。 用于研究 FoxO1 和 Fst 是否通过肝脏果糖代谢促进 NAFLD/NASH。 循环脂肪酸与肝 Gro3P（3-磷酸甘油）（一种果糖代谢物）的酯化是一种 NAFLD 患者肝脏三酰甘油的主要来源 了解果糖是否会促进 NAFLD 患者的肝脏代谢。 NAFLD/NASH 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 研究在未删除肝脏 FoxO1 或 Fst 或 Khk 的情况下或删除后饲喂 HFruD60% 的 LDKO 小鼠 （酮己糖激酶）对果糖的肝脏代谢至关重要，喂养小鼠 [13C] 果糖可实现 LC-。 MS 测定果糖代谢物与肝脏或肝脏的甘油或脂肪酸部分的结合情况 在人类和小鼠中，循环三酰甘油可能是由“选择性胰岛素抵抗”引起的。 然而，我们认为，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； 选择性肝胰岛素抵抗可能会产生相反的效果并减弱 NAFLD/NASH 抑制 FoxO1 和 Fst 由于慢性营养过剩会抑制肝脏 Irs2，因此我们研究了 GAN 饮食 - 在缺乏肝脏 Irs2（LKO2 小鼠）或 Irs1（LKO1 小鼠）的小鼠中诱导 NAFLD/NASH 和 T2D，以及我们的 在肝细胞中表达营养不敏感的 Irs2tg 的新型转基因小鼠可以完成我们的建议。 通过确定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。