Role of SIRT3 in Modulation of Lipotoxicity in Liver

SIRT3 在肝脏脂毒性调节中的作用

基本信息

批准号：
8312408
负责人：
Sean A. Newsom
金额：
$ 4.71万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8312408
关键词：
Acetylation Adenoviruses Adult Affect Aging Antioxidants Apoptosis Attenuated Biochemical Caloric Restriction Data Deacetylation Development Diet Disease Disease susceptibility Enzymes Epidemic Fatty Liver Fatty acid glycerol esters Gene Transfer Genes Genome Stability Gluconeogenesis Goals Health Hepatic Impairment Infection Insulin Resistance Knockout Mice Laboratories Lead Link Lipids Liver Liver Dysfunction Liver Mitochondria Liver diseases Longevity Malignant Neoplasms Mediating Metabolic Metabolic Control Metabolic Diseases Metabolic stress Metabolism Mitochondria Mitochondrial Matrix Mitochondrial Proteins Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Family Nutrient Nutrition Disorders Obesity Oxidative Stress Pattern Play Predisposition Production Protein Acetylation Proteins Proteomics Publishing Regulation Reporting Role Secondary to Set protein Sir2-like Deacetylases Sirtuins Stress Testing Transcriptional Regulation Virus Work design feeding gain of function glucose metabolism glucose production in vivo insulin sensitivity lipid metabolism liver function mitochondrial dysfunction nicotinamide phosphoribosyltransferase non-alcoholic fatty liver obesity in children overexpression oxidation oxidative damage protein function response restoration

项目摘要

DESCRIPTION (provided by applicant): Sirtuins are NAD+-dependent protein deacetylases that mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. Sirtuin 3 (SIRT3) is localized within the mitochondrial matrix, where it regulates acetylation levels of a diverse set of metabolic enzymes. Although well characterized in models of caloric restriction, relatively little is known about the role of Sirtuins and acetylaion under conditions of caloric excess. Our recent results show that when normal mice are fed a high fat diet they demonstrate reduced SIRT3 activity, impaired mitochondrial function, and hyperacetylation of a diverse set of proteins, including gluconeogenic enzymes, in their livers. Furthermore, SIRT3 knockout mice have signs of accelerated aging and cancer. Understanding SIRT3's biochemical function and regulation in the liver under conditions of caloric excess may potentially help explain the connection between reduced mitochondrial function and disorders of lipid and glucose metabolism, such as type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). The immediate purpose of this proposal is two-fold: 1) determine if restoration of hepatic SIRT3 activity during high fat feeding can attenuate the progression of obesity- related steatosis or hepatic insulin resistance, and 2) Determine whether increasing hepatic NAD+, the major determinant of SIRT3 activity, will attenuate obesity-linked mitochondrial ROS and protein acetylation. The long-term goal of this project is to dissect the mechanisms surrounding how excess nutrients lead to hyperacetylation of key proteins and to identify a regulatory role for SIRT3 in NAFLD and susceptibility to type 2 diabetes. PUBLIC HEALTH RELEVANCE: Nonalcoholic fatty liver disease (NAFLD) is the most common nutritional disorder, currently affecting 50 percent of obese adults and 1/3 of obese children. Recent findings indicate that Sirtuin 3 (SIRT3) may play an important role linking hepatic fuel metabolism and mitochondrial health. The studies proposed here will investigate the role of SIRT3 as a promising target to protect against obesity-induced metabolic complications, including NAFLD. Findings from these studies will resolve whether altered SIRT3 activity contributes to the progression of obesity-induced liver steatosis, insulin resistance, and mitochondrial dysfunction, and determine if increasing SIRT3 activity can protect against (or at least minimize) these complications, providing valuable information for developing treatments for NAFLD.

描述（由申请人提供）：Sirtuins是NAD+依赖性蛋白脱乙酰基酶，可介导对各种应激的适应性反应，包括卡路里限制和代谢应激。 SIRTUIN 3（SIRT3）位于线粒体基质中，它调节了多种代谢酶的乙酰化水平。尽管在热量限制的模型中表现出良好的特征，但对于sirtuins和acetylaion在热量过量条件下的作用知之甚少。我们最近的结果表明，当正常小鼠喂养高脂肪饮食时，它们表现出降低的SIRT3活性，线粒体功能受损以及多种蛋白质（包括糖原性酶）在其肝脏中的多种蛋白质的高乙酰化。此外，SIRT3敲除小鼠具有加速衰老和癌症的迹象。了解SIRT3在热量过量条件下肝脏中SIRT3的生化功能和调节可能有助于解释降低的线粒体功能与脂质和葡萄糖代谢的疾病之间的联系，例如2型糖尿病和非酒精脂肪脂肪肝疾病（NAFLD）。该提案的直接目的是两倍：1）确定在高脂肪进食过程中肝SIRT3活性的恢复是否可以减弱与肥胖相关的脂肪变性或肝胰岛素耐药性的进展，以及2）确定肝NAD+的增加，确定SIRT3活性的增加（SIRT3活性）是否会降低肥胖剂量的主要确定性，会衰减蛋白质粒粒度和蛋白质蛋白质粒粒粒粒粒粒粒粒粒粒粒粒粒粒粒粒粒粒粒跟踪。该项目的长期目标是剖析围绕多余营养导致关键蛋白过度乙酰化的机制，并确定SIRT3在NAFLD中的调节作用以及对2型糖尿病的敏感性。公共卫生相关性：非酒精性脂肪肝病（NAFLD）是最常见的营养疾病，目前影响50％的肥胖成年人和1/3的肥胖儿童。最近的发现表明，Sirtuin 3（SIRT3）可能在将肝燃料代谢和线粒体健康联系起来起着重要作用。这里提出的研究将研究SIRT3作为预防肥胖引起的代谢并发症（包括NAFLD）的有希望的目标。这些研究的结果将解决SIRT3活性改变是否有助于肥胖引起的肝脏脂肪变性，胰岛素抵抗和线粒体功能障碍的进展，并确定SIRT3活性增加可以防止（或至少最小化）这些并发症，从而为NAFLD提供了有价值的处理信息。