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.

项目概要/摘要 与酒精相关的疾病，包括非酒精性脂肪肝（NAFLD）和糖尿病， 传染病是发达国家的主要死因。迫切需要确定 新的分子靶点，可能导致更好的治疗和诊断策略，用于管理 这些疾病。许多研究表明，丝氨酸代谢的改变与NAFLD有关。 这些观察结果提出了一种有趣的可能性，即异常的细胞分裂与细胞分裂之间可能存在因果关系。 丝氨酸代谢和疾病的发展。我们的研究表明，SHMT 2的表达， 丝氨酸分解代谢酶，在高脂肪饮食喂养的啮齿动物模型的肝脏中显著降低， 这表明肝丝氨酸催化剂在对热量过量的反应中减少。丝氨酸催化剂 产生重要的代谢中间产物，包括一碳单元和甘氨酸。最近，我们和其他 已经报道了SHMT 2的失活导致哺乳动物细胞中线粒体呼吸受损。 从机制上讲，我们已经进一步证明了SHMT 2介导的丝氨酸催化剂提供了一个- 碳代谢物的组装必不可少的呼吸复合物I，门控酶的 线粒体呼吸链此外，我们发现SHMT 2的靶向缺失导致了显著的 肝细胞系中脂肪积累增加和关键β-氧化基因表达降低。鉴于 线粒体功能障碍对许多代谢性疾病的病因学有重要影响， NAFLD，我们提出了一种机制模型，其中肝脏SHMT 2表达减少导致受损的 线粒体呼吸，从而增加了肝脂肪变性和胰岛素抵抗， 衰老过程中的营养过剩这个项目的首要目标是测试这个模型，并确定是否有 丝氨酸代谢和NAFLD易感性之间的因果关系。这将通过 表征实验性改变的肝脏SHMT 2基因表达在瘦肉型和 肥胖小鼠这些研究代表了探索新的和潜在的重要可能性的初步努力 肝丝氨酸催化剂影响疾病易感性，如果这是真的，将确定SHMT 2作为一个潜在的 NAFLD和其他年龄相关疾病治疗干预的目标。