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-羟基壬烯醛 (4-HNE) 是一种信号分子，影响包括衰老在内的多种基本生物过程。在生成 4-HNE 代谢受损的基因敲除小鼠时，我们发现 4-HNE 升高会导致肥胖表型。我们还在线虫中观察到由于 4-HNE 代谢沉默或直接暴露于 4-HNE 引起的脂肪积累增加，证实 4-HNE 触发的脂肪积累在系统发育上是保守的。在小鼠中，4-HNE 升高与年龄依赖性胰岛素抵抗的出现有关，这种情况可能会缩短寿命。我们直接观察到 4-HNE 引发的脂肪积累导致线虫寿命缩短。因此，干扰4-HNE信号传导（否则会导致脂肪堆积）不仅有可能减轻肥胖，而且有可能预防对公共健康有重大影响的疾病，例如胰岛素抵抗和糖尿病，以及与年龄相关的疾病。在设计干预措施来抵消 4-HNE 的这些有害影响之前，有必要了解 4-HNE 导致肥胖的机制。我们假设这些机制包括乙酰辅酶 A 羧化酶 (ACC) 的激活，并且已经证实了在 4-HNE 组织水平增加的小鼠和蠕虫中丙二酰辅酶 A 升高的预测。众所周知，丙二酰辅酶A升高会通过增加脂肪酸生物合成和抑制脂肪酸β-氧化而导致肥胖。我们将在两个互补的实验系统中检验我们的假设，即 4-HNE 调节 ACC 活性：基因敲除小鼠（因为小鼠和人类生理学之间的相似性）和秀丽隐杆线虫（因为其遗传和生化易处理性、易于衰老研究以及一般性研究）。线虫和哺乳动物之间脂肪相关代谢的保守）。然后，我们将在人类细胞系中测试根据这一假设得出的主要预测。拟议研究的具体目标是 (1) 测量小鼠组织中代谢物水平和酶活性的变化，以确定 4-HNE 是否通过增加柠檬酸等变构激活剂和/或降低 ACC 磷酸化来调节 ACC。 4-HNE 水平升高的小鼠的寿命也将被确定； (2) 从基因角度操纵秀丽隐杆线虫调节丙二酰辅酶A的酶，以确定4-HNE作用的精确机制，并确定4-HNE对长寿的影响是由脂肪积累介导的还是独立于脂肪积累； (3) 测试在动物模型中观察到的 4-HNE 引发的脂肪储存机制是否适用于人类生物学。公共卫生相关性：与代谢综合征相关的疾病给个人和社会造成的损失是巨大的。我们建议定义一种介导代谢综合征发展并同时促进衰老的分子机制。未来基于所获得知识的干预措施可能会延迟这些情况的发生。