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: 8545824
• 负责人: GERALD I SHULMAN
• 金额: $ 121.97万
• 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/8545824
• 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），非酒精脂肪肝疾病（NAFLD）及其相关的合作率正在成为美国最重要的医疗保健问题。我们小组的最新研究已经在成人和儿童的肝胰岛素抵抗和T2DM的发病机理中确立了NAFLD的关键作用。我们组对转基因和基因敲除小鼠的互补研究阐明了与NAFLD相关的肝胰岛素抵抗的分子机制。在这个R-24中，有一个跨学科和独立调查员的团队拥有既定的协作记录，他们将解决有关这两个日益普遍的条件之间关系的基本问题。具体而言，这支跨学科科学家团队将研究谁开发NAFLD的复杂且相关的问题，NAFLD如何引起肝胰岛素抵抗，这会触发T2DM中肝糖糖的增加，以及在Roux-y-y-y-y-y-y-y-y-y-y-y-y-y-y gastric bypass（rygb）下（rygb）的多个变化如何迅速解决，甚至在实质性的下降（rygb），甚至如何迅速解决？具体而言，我们将研究：1）与NAFLD和T2DM相关的肝胰岛素抵抗的分子机制，并增加了肝糖异生。 2）特定基因变异在载脂蛋白C3中的作用在NAFLD和肝胰岛素抵抗的发病机理中。 3）在roux-en-y胃旁路后，导致胰岛素抵抗和T2DM逆转的细胞和分子机制。这项提案以研究人员之间跨学科合作的既定记录以及25年的历史以及实施新型的最先进的MRS/MRI/MRI和稳定的同位素方法来建立，用于非侵袭性评估人类的肝葡萄糖和脂质代谢。预计拟议研究的结果将改变当前的范式，以理解NAFLD，肝胰岛素抵抗和T2DM的发病机理。 公共卫生相关性：该跨学科的团队科学计划将研究2型糖尿病和非酒精脂肪肝病的发病机理，这些疾病迅速成为成人和儿童二十一世纪最大的全球健康挑战。