Causative role of lipid peroxidation products in obesity and aging

脂质过氧化产物在肥胖和衰老中的致病作用

基本信息

批准号：
7729405
负责人：
Piotr Zimniak
金额：
$ 25.3万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7729405
关键词：
4 hydroxynonenal Acetyl Coenzyme A Acetyl-CoA Carboxylase Aconitate Hydratase Address Adipocytes Affect Age Aging Animal Model Animals Biochemical Biological Process Caenorhabditis elegans Candidate Disease Gene Cells Chemical Structure Citrates Citric Acid Cycle Coenzyme A Complex Cost of Illness Data Deposition Development Diabetes Mellitus Disease Eating Endocrine Enzymes Etiology Exposure to Famines Fatty Acids Fatty acid glycerol esters Figs - dietary Future Genes Genetic Gray unit of radiation dose Hepatocyte Hormonal Human Human Biology Human Cell Line Inflammation Insulin Resistance Intervention Knockout Mice Knowledge Lead Learning Life Link Lipid Peroxidation Lipids Literature Location Longevity Malonyl Coenzyme A Mammals Measures Mediating Metabolic Metabolic syndrome Metabolism Mission Molecular Mus National Institute on Aging Nature Nematoda Neurosecretory Systems Obesity Organism Pathway interactions Phenotype Phosphorylation Phosphotransferases Physiological Physiology Play Premature aging syndrome Process Production Proteins Public Health Publishing Role Scheme Signal Transduction Signaling Molecule Site System Testing Text Thioctic Acid Time Tissue Harvesting Tissues Ursidae Family Wild Type Mouse Withdrawal Work adiponectin age effect age related base cofactor enzyme activity fatty acid biosynthesis knock-down overexpression oxidation prevent protective effect public health relevance upstream kinase

项目摘要

DESCRIPTION (provided by applicant): The lipid peroxidation product 4-hydroxynonenal (4-HNE) is a signaling molecule affecting several fundamental biological processes, including aging. In generating a knockout mouse with impaired 4-HNE metabolism, we found that elevated 4-HNE causes an obese phenotype. We also observed increased fat accumulation caused by either silencing of 4-HNE metabolism or by direct exposure to 4-HNE in the nematode C. elegans, establishing that 4-HNE-triggered fat accretion is phylogenetically conserved. In mice, elevated 4-HNE is associated with age-dependent emergence of insulin resistance, a condition that could curtail life span. We directly observed shortened life span in C. elegans with 4-HNE-triggered fat accumulation. Therefore, interference with 4-HNE signaling that would otherwise cause fat accumulation has the potential not only to alleviate obesity, but also to prevent conditions with high public health impact such as insulin resistance and diabetes, as well as age-associated diseases. Before interventions can be devised to counteract these detrimental effects of 4-HNE, it is necessary to understand the mechanisms by which 4-HNE contributes to obesity. We hypothesize that these mechanisms include activation of acetyl-CoA carboxylase (ACC), and have already confirmed the resulting prediction of elevated malonyl-CoA in mice and worms with increased tissue levels of 4-HNE. It is known that elevated malonyl-CoA leads to obesity via an increase in fatty acid biosynthesis and inhibition of fatty acid beta-oxidation. We will test our hypothesis that 4-HNE modulates ACC activity, in two complementary experimental systems: knockout mice (because of similarities between murine and human physiology) and C. elegans (because of its genetic and biochemical tractability, facile aging studies, and general conservation of fat-related metabolism between nematodes and mammals). We will then test the major predictions following from this hypothesis in human cell lines. The Specific Aims of the proposed studies are (1) to measure, in mouse tissues, changes in metabolite levels and enzyme activities to determine whether 4-HNE modulates ACC by increasing its allosteric activators such as citrate, and/or by decreasing ACC phosphorylation. The life span of mice with increased 4-HNE levels will be also determined; (2) to manipulate genetically C. elegans enzymes that modulate malonyl-CoA to define the precise mechanism of 4-HNE action and to determine whether the effect of 4-HNE on longevity is mediated by, or independent of fat accumulation; and (3) to test whether the mechanism of 4-HNE-triggered fat storage observed in animal models applies to human biology PUBLIC HEALTH RELEVANCE: The personal and societal costs of diseases related to metabolic syndrome are enormous. We propose to define a molecular mechanism that mediates the development of metabolic syndrome and, at the same time, contributes to aging. Future interventions based on the knowledge to be gained may delay the onset of these conditions.

描述（由申请人提供）：脂质过氧化产物4-羟基诺纳尔（4-HNE）是一个信号分子，影响包括衰老在内的几个基本生物学过程。在产生具有4-HNE代谢受损的敲除小鼠时，我们发现升高的4-HNE会导致肥胖表型。我们还观察到，由于4-HNE代谢的沉默或直接暴露于线虫C.秀丽隐杆线虫中的4-HNE引起的脂肪积累增加，并确定4-HNE触发的脂肪积聚是系统发育的。在小鼠中，升高的4-HNE与胰岛素抵抗的年龄依赖性出现有关，这种疾病可能会减少寿命。我们直接观察到秀丽隐杆线虫的寿命缩短，其4-HNE触发的脂肪积累。因此，对否则会导致脂肪积累的4-HNE信号的干扰不仅可以减轻肥胖症，而且还可以预防具有巨大公共卫生影响的状况，例如胰岛素抵抗和糖尿病以及与年龄相关的疾病。在设计干预措施以抵消4-HNE的这些有害作用之前，有必要了解4-HNE对肥胖有效的机制。我们假设这些机制包括激活乙酰-COA羧化酶（ACC），并且已经证实了小鼠和蠕虫的丙酰coA升高的预测，而组织水平升高了4-HNE。众所周知，丙二酰辅酶A升高会通过脂肪酸生物合成和抑制脂肪酸β-氧化的抑制而导致肥胖。我们将测试我们的假设，即4-HNE在两个互补的实验系统中调节ACC活性：基因敲除小鼠（由于鼠和人类生理学之间的相似性）和秀丽隐杆线虫（由于其遗传和生化易生化研究，便利化的衰老研究，以及对Nematodes和Mamalmals and Mamamals之间的脂肪相关代谢性的一般保存）。然后，我们将根据人类细胞系中的假设来测试主要预测。拟议研究的具体目的是（1）在小鼠组织中测量代谢物水平和酶活性的变化，以确定4-HNE是否通过增加其变构激活剂（如柠檬酸盐）和/或降低ACC磷酸化来调节ACC。还将确定升高4-HNE水平的小鼠的寿命；（2）操纵遗传秀丽隐杆线虫酶，以调节丙二酰辅酶A定义4-HNE作用的确切机制，并确定4-HNE对寿命的影响是由寿命的影响是由脂肪积累介导的还是独立于脂肪的；（3）测试动物模型中观察到的4-HNE触发脂肪存储的机制是否适用于人类生物学公共卫生相关性：与代谢综合征有关的疾病的个人和社会成本是巨大的。我们建议定义一种分子机制，该机制介导了代谢综合征的发展，同时又有助于衰老。基于要获得的知识的未来干预措施可能会延迟这些条件的发作。