Genetic and Cellular Mechanisms of NAFLD and Hepatic Insulin Resistance

NAFLD 和肝胰岛素抵抗的遗传和细胞机制

• 批准号: 8310171
• 负责人: GERALD I SHULMAN
• 金额: $ 127.1万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8310171
• 关键词: 1,2-diacylglycerol; Accounting; Address; Adult; Apolipoproteins; Body Weight decreased; Ceramides; Child; Collaborations; Comorbidity; Complex; Data; Development; Diglycerides; Discipline; Fatty Acids; Gastric Bypass; Genes; Genetic; Genetic Variation; Gluconeogenesis; Glucose; Grant; Healthcare; Hepatic; Human; Hyperglycemia; Insulin; Insulin Resistance; Knockout Mice; Lipids; Liver; Liver diseases; Magnetic Resonance Imaging; Methodology; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Pathogenesis; Pathway interactions; Patients; Phosphoenolpyruvate Carboxylase; Plasma; Prevalence; Principal Investigator; Protein Isoforms; Pyruvate Carboxylase; Recording of previous events; Research Personnel; Resistance; Role; Science; Scientist; Skeletal Muscle; Steatohepatitis; Stress; Transgenic Organisms; Triglycerides; Variant; bariatric surgery; global health; glucose metabolism; glucose-6-phosphatase; hepatic gluconeogenesis; insulin signaling; interdisciplinary collaboration; lipid metabolism; non-alcoholic fatty liver; novel; programs; protein expression; public health relevance; stable isotope

DESCRIPTION (provided by applicant): Type 2 diabetes mellitus (T2DM), Non Alcoholic Fatty Liver Disease (NAFLD), and their associated co- morbidities, are emerging as the most important health care problems in the USA. Recent studies by our group have established a key role for NAFLD in the pathogenesis of hepatic insulin resistance and T2DM in both adults and children. Complementary studies in transgenic and gene knockout mice by our group have elucidated the molecular mechanism for hepatic insulin resistance associated with NAFLD. In this R-24 grant a team of interdisciplinary and independent investigators, who have an established track record of collaboration, will address fundamental questions regarding the relationship between these two increasingly prevalent conditions. Specifically, this team of interdisciplinary scientists will examine the complex and related problems of who develops NAFLD, how does NAFLD cause hepatic insulin resistance, what triggers the increased hepatic gluconeogenesis in T2DM, and how do many of these changes rapidly resolve following Roux-en-Y gastric bypass (RYGB), even before substantial weight loss? Specifically we will examine: 1) The molecular mechanisms of hepatic insulin resistance and increased hepatic gluconeogenesis associated with NAFLD and T2DM. 2) The role of specific gene variants in apolipoprotein C3 in the pathogenesis of NAFLD and hepatic insulin resistance. 3) The cellular and molecular mechanisms responsible for the reversal of insulin resistance and T2DM following Roux-en-Y gastric bypass. This proposal builds on an established track record of interdisciplinary collaboration among the investigators as well as a 25-year history of developing and implementing novel state-of-the-art MRS/MRI and stable isotope methodologies for noninvasively assessing hepatic glucose and lipid metabolism in humans. It is anticipated that the results from the proposed studies will shift the current paradigm in our understanding of the pathogenesis of NAFLD, hepatic insulin resistance and T2DM. PUBLIC HEALTH RELEVANCE: This interdisciplinary team science program will examine the pathogenesis of type 2 diabetes mellitus and non alcoholic fatty liver disease, which are rapidly emerging as the greatest global health challenges of the twenty-first century in both adults and children.

描述（由申请人提供）：2 型糖尿病 (T2DM)、非酒精性脂肪肝病 (NAFLD) 及其相关合并症正在成为美国最重要的医疗保健问题。我们小组最近的研究已经确定 NAFLD 在成人和儿童肝脏胰岛素抵抗和 T2DM 的发病机制中发挥着关键作用。我们小组对转基因和基因敲除小鼠的补充研究阐明了与 NAFLD 相关的肝脏胰岛素抵抗的分子机制。在这项 R-24 拨款中，一个由跨学科和独立研究人员组成的团队（他们拥有良好的合作记录）将解决有关这两种日益普遍的疾病之间关系的基本问题。具体来说，这个由跨学科科学家组成的团队将研究复杂且相关的问题，包括谁会患上 NAFLD、NAFLD 如何导致肝脏胰岛素抵抗、是什么触发了 T2DM 中肝脏糖异生的增加，以及这些变化如何在 Roux-en 后迅速解决。 Y 胃绕道手术（RYGB），甚至在大幅减肥之前？具体来说，我们将检查：1) 与 NAFLD 和 T2DM 相关的肝脏胰岛素抵抗和肝脏糖异生增加的分子机制。 2）载脂蛋白C3特定基因变异在NAFLD和肝胰岛素抵抗发病机制中的作用。 3) Roux-en-Y胃绕道手术后逆转胰岛素抵抗和T2DM的细胞和分子机制。该提案建立在研究人员之间跨学科合作的既定记录以及开发和实施新型最先进的 MRS/MRI 和稳定同位素方法以无创评估肝脏葡萄糖和脂质代谢的 25 年历史的基础上。人类。预计所提出的研究结果将改变我们目前对 NAFLD、肝胰岛素抵抗和 T2DM 发病机制的理解范式。 公共健康相关性：这个跨学科团队科学项目将研究 2 型糖尿病和非酒精性脂肪肝疾病的发病机制，这些疾病正在迅速成为 21 世纪成人和儿童面临的最大全球健康挑战。