Role of serine catabolism in age-related metabolic diseases

丝氨酸分解代谢在年龄相关代谢疾病中的作用

• 批准号: 9806315
• 负责人: Jian Wang
• 金额: $ 23.1万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9806315
• 关键词: Affect; Aging; Animal Model; Carbon; Catabolism; Cause of Death; Cell Line; Communicable Diseases; Complex; Developed Countries; Developing Countries; Development; Diabetes Mellitus; Diagnostic; Disease; Disease Management; Disease susceptibility; Enzymes; Etiology; Event; Fatty Liver; Fatty acid glycerol esters; Folic Acid; Gatekeeping; Gene Expression; Generations; Genes; Glycine; Glycine Hydroxymethyltransferase; Goals; Hepatic; Hepatocyte; High Fat Diet; Human Pathology; Human body; Hygiene; Impairment; In Vitro; Individual; Insulin Resistance; Intervention; Knock-out; Lead; Link; Lipids; Liver; Maintenance; Mammalian Cell; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Mitochondria; Modeling; Molecular; Molecular Target; Mus; NADH dehydrogenase (ubiquinone); Nutritional; Obese Mice; Obesity; Overnutrition; Pathogenesis; Pathway interactions; Physiological; Prevention; Process; Protein Isoforms; Proteins; Reporting; Resistance development; Respiration; Respiratory Chain; Respiratory physiology; Risk; Rodent Model; Role; Serine; Source; Testing; Therapeutic; Therapeutic Intervention; Thinness; Tissue Sample; adeno-associated viral vector; age related; base; genetic approach; human model; improved; liver injury; metabolic phenotype; mitochondrial dysfunction; non-alcoholic fatty liver disease; novel; nutritional supplementation; oxidation; response; restoration; targeted treatment; treatment strategy

Project Summery/Abstract Age-related disorders including non-alcoholic fatty liver disease (NAFLD) and diabetes have replaced infectious diseases as the leading cause of death in developed countries. There is a pressing need to identify novel molecular targets that could lead to better therapeutic and diagnostic strategies for the management of these diseases. Numerous studies have demonstrated that altered serine metabolism is linking to NAFLD. These observations raise the intriguing possibility that there may be a causal relationship between aberrant serine metabolism and the development of the disease. Our studies show that the expression of SHMT2, a serine catabolic enzyme, is significantly reduced in the livers of the rodent models fed with high fat diet, suggesting that hepatic serine catabolism is reduced in response to caloric excess. Serine catabolism produces important metabolic intermediates including one-carbon unit and glycine. Recently, we and others have reported that inactivation of SHMT2 leads to impaired mitochondrial respiration in mammalian cells. Mechanistically, we have further demonstrated that SHMT2-mediated serine catabolism supplies the one- carbon metabolite essential for the assembly of respiratory Complex I, the gatekeeper enzyme of the mitochondrial respiratory chain. In addition, we found that targeted deletion of SHMT2 resulted in significantly increased fat accumulation and decreased expression of key -oxidation genes in hepatic cell line. Given the significant impact of mitochondrial dysfunction on the etiology of a number of metabolic diseases including NAFLD, we propose a mechanistic model where decreased hepatic SHMT2 expression leads to impaired mitochondrial respiration and thus increased hepatic steatosis and insulin resistance in individuals with overnutrition during aging. The overarching goal of this project is to test this model and determine if there is a causal link between serine metabolism and NAFLD susceptibility. This will be accomplished by characterizing the metabolic effects of experimentally altered hepatic SHMT2 gene expression in lean and obese mice. These studies represent an initial effort to explore the novel and potentially important possibility that hepatic serine catabolism affects disease susceptibility, which if true, would identify SHMT2 as a potential target for therapeutic intervention for NAFLD and other age-related diseases.

项目夏季/摘要 与年龄有关的疾病，包括非酒精性脂肪肝病（NAFLD）和糖尿病 传染病是发达国家死亡的主要原因。迫切需要识别 新的分子靶标可以为管理提供更好的治疗和诊断策略 这些疾病。许多研究表明，改变的丝氨酸代谢与NAFLD有关。 这些观察结果提出了一种有趣的可能性，即异常之间可能存在因果关系 连续代谢和疾病的发展。我们的研究表明，SHMT2的表达 丝氨酸分解代谢酶在用高脂肪饮食的啮齿动物模型的生活中显着降低， 表明肝丝氨酸的分解代谢响应过量而降低。丝氨酸分解代谢 产生重要的代谢中间体，包括一碳单位和甘氨酸。最近，我们和其他人 据报道，SHMT2失活导致哺乳动物细胞中线粒体呼吸受损。 从机械上讲，我们进一步证明了SHMT2介导的丝氨酸分解代谢提供了一种 碳代谢物对于组装呼吸道I的必不可少 线粒体呼吸链。此外，我们发现针对SHMT2的靶向缺失显着导致 肝细胞系中关键氧化基因的脂肪积累增加和降低的表达。鉴于 线粒体功能障碍对多种代谢疾病的病因的重大影响 NAFLD，我们提出了一个机械模型，其中肝脏SHMT2表达降低会导致受损 线粒体呼吸，从而增加了患有 衰老期间的营养。该项目的总体目标是测试该模型并确定是否存在 丝氨酸代谢与NAFLD敏感性之间的因果关系。这将通过 表征实验改变的肝脏SHMT2基因表达的代谢作用 肥胖的老鼠。这些研究代表了探索新颖和潜在重要可能性的初步努力 肝炎丝氨酸的分解代谢会影响疾病的敏感性，如果是的，则会将SHMT2识别为潜在 针对NAFLD和其他年龄有关疾病的治疗干预措施的靶标。