Role of serine catabolism in age-related metabolic diseases

项目摘要/摘要 与年龄相关的疾病，包括非酒精性脂肪性肝病(NAFLD)和糖尿病，已经被取代 在发达国家，传染病是主要的死亡原因。迫切需要找出 可能导致更好的治疗和诊断策略的新的分子靶点 这些疾病。大量研究表明，丝氨酸代谢的改变与NAFLD有关。 这些观察提出了一种耐人寻味的可能性，即异常之间可能存在因果关系 丝氨酸代谢与疾病的发展。我们的研究表明，SHMT2、a的表达 高脂饲料喂养的啮齿类动物肝脏中丝氨酸分解代谢酶显著降低， 提示肝脏丝氨酸分解代谢减少是对热量过剩的反应。丝氨酸分解代谢 产生重要的代谢中间产物，包括一碳单位和甘氨酸。最近，我们和其他人 有报道称，SHMT2失活会导致哺乳动物细胞线粒体呼吸功能受损。 从机制上，我们进一步证明了SHMT2介导的丝氨酸分解代谢提供了一种- 碳代谢产物对呼吸复合体I的组装至关重要，I是呼吸系统的守门酶 线粒体呼吸链。此外，我们发现，SHMT2的靶向删除导致了显著的 肝细胞系脂肪蓄积增加，关键氧化基因表达减少。给定 线粒体功能障碍对许多代谢性疾病的病因有重大影响，包括 NAFLD，我们提出了一个机制模型，其中肝脏SHMT2表达降低导致受损 线粒体呼吸，从而增加肝脏脂肪变性和胰岛素抵抗 衰老过程中的营养过剩。该项目的总体目标是测试该模型，并确定是否存在 丝氨酸代谢和NAFLD易感性之间的因果联系。这将通过以下方式实现 实验改变瘦肉型和肉仔鸡肝脏SHMT2基因表达的代谢效应 肥胖的老鼠。这些研究代表了探索这一新颖和潜在的重要可能性的初步努力 肝脏丝氨酸分解代谢影响疾病的易感性，如果这是真的，将确定SHMT2是一种潜在的 NAFLD和其他年龄相关疾病的治疗干预目标。

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.