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（T2 DM）、非酒精性脂肪肝（NAFLD）及其相关共病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了NAFLD在成人和儿童肝脏胰岛素抵抗和T2 DM发病机制中的关键作用。我们小组在转基因和基因敲除小鼠中的补充研究已经阐明了与NAFLD相关的肝脏胰岛素抵抗的分子机制。在这项R-24资助中，一个跨学科和独立的研究人员团队，他们有着良好的合作记录，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，这个跨学科的科学家团队将研究谁发展NAFLD的复杂和相关问题，NAFLD如何引起肝脏胰岛素抵抗，是什么触发了T2 DM中肝脏异生的增加，以及这些变化中的许多如何在Roux-en-Y胃旁路术（RYGB）后迅速解决，甚至在体重大幅减轻之前？具体来说，我们将研究：1）NAFLD和T2 DM相关的肝脏胰岛素抵抗和肝脏新生血管增加的分子机制。2)载脂蛋白C3特异性基因变异在NAFLD和肝脏胰岛素抵抗发病机制中的作用3)Roux-en-Y胃旁路术后胰岛素抵抗和T2 DM逆转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MRS/MRI和稳定同位素方法的25年历史的基础上，用于非侵入性评估人类肝脏葡萄糖和脂质代谢。预计拟议研究的结果将改变我们对NAFLD、肝胰岛素抵抗和T2 DM发病机制的理解。 公共卫生相关性：这个跨学科的团队科学计划将研究2型糖尿病和非酒精性脂肪肝的发病机制，这些疾病正在迅速成为二十一世纪成人和儿童面临的最大全球健康挑战。