Sulfur Amino Acid Metabolism and Regulation of Hepatic Metabolic Flexibility

硫氨基酸代谢和肝脏代谢灵活性的调节

• 批准号: 10538622
• 负责人: Tiangang Li
• 金额: $ 41.21万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10538622
• 关键词: Alcoholic Liver Cirrhosis; Animal Model; Attenuated; Automobile Driving; Basic Science; Bile Acids; Cholestasis; Coenzyme A; Complex; Cysteine; Cysteine dioxygenase; Defect; Diet; Enzymes; Essential Amino Acids; Etiology; Fasting; Fatty Acids; Fatty acid glycerol esters; Fibroblast Growth Factor; Future; Genetic; Glutathione; Goals; Hepatic; Hepatocyte; Homeostasis; Human; Impairment; Inflammation; Injury; Knockout Mice; Knowledge; Link; Liver; Liver diseases; Malignant neoplasm of liver; Mediating; Metabolic; Metabolism; Methionine; Mitochondria; Molecular; Molecular Target; Mus; Nutrient; Organ; Output; Oxidative Stress; Pathogenicity; Physiological; Physiology; Predisposition; Regulation; Reporting; Role; Severities; Severity of illness; Signal Transduction; Stress; Sulfur; Sulfur Amino Acids; Taurine; Testing; Therapeutic Intervention; Transgenic Mice; Up-Regulation; Virulence Factors; amino acid metabolism; clinically significant; fatty acid oxidation; fatty liver disease; flexibility; gain of function; human model; improved; insight; lipid metabolism; loss of function; methionine adenosyltransferase; mitochondrial dysfunction; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; preservation; therapeutic target; transcription factor

Project summary It is increasingly recognized that non-alcoholic steatohepatitis (NASH) is a prevalent liver disease with complex and heterogenous underlying causes. Now, new evidence suggests that dysregulated hepatic sulfur amino acid metabolism is associated with advanced human NASH and causes markedly worsened steatosis and injury in genetic mouse models. However, significant knowledge gaps exist in our understanding of how sulfur amino acid metabolism modifies NASH severity, and what mechanisms control hepatic sulfur amino acid metabolism in normal physiology and liver diseases. This proposal builds on our discovery that CoA metabolism is a key missing link between impaired hepatic sulfur amino acid metabolism and liver fat accumulation and injury in NASH. We aim to establish a novel pathogenic mechanism whereby hepatic availability of cysteine (a CoA synthesis substrate) is critical in maintaining the mitochondrial CoA pool to support fatty acid oxidation. However, dysregulated sulfur amino acid flux in advanced NAFLD reduces cysteine availability that impairs CoA synthesis. Hepatic CoA insufficiency in turn limits the liver’s ability to adapt to increased fatty acid influx, creating a condition termed metabolic inflexibility that promotes mitochondrial dysfunction, steatosis and oxidative stress. Mechanistically, we have identified that impaired methionine adenosyltransferase 1A (MAT1A), which drives upstream methionine cycle-transsulfuration flux to produce cysteine, and overactivation of cysteine dioxygenase type-1 (CDO1), which mediates downstream cysteine elimination, contribute to such pathogenic condition by causing imbalanced cysteine input and output in NAFLD. Further study revealed intriguing crosstalk of bile acids, TFEB, and FGF15/19 signaling regulation of MAT1A and CDO1 to control hepatic sulfur amino acid and CoA metabolism under normal physiology and NASH. We have developed novel mouse models that allow us to manipulate hepatic sulfur amino acid flux at the two key regulatory steps (MAT1A, CDO1). In Aim 1, we will use hepatocyte-specific inducible CDO1 transgenic mice and hepatocyte-specific CDO1 knockout mice to study how altered CDO1 expression downstream of bile acid signaling impacts hepatic sulfur amino acid, CoA and GSH metabolism to modulate NASH severity. In Aim 2, we will use liver specific MAT1A gain-of-function and loss-of-function mouse models to establish the significance of the MAT1A in regulating hepatic sulfur amino acid, CoA and GSH metabolism, and further investigate how FGF15/19 and TFEB regulate MAT1A-driven sulfur flux and CoA metabolism in physiology and NASH. By defining a new pathogenic link of sulfur amino acid metabolism to CoA metabolism and delineating novel mechanisms regulating hepatic sulfur amino acid and CoA metabolism, we expect that this study may advance the field by providing not only new insights into the mechanisms driving NASH progression but also molecular basis for developing future therapeutic interventions.

项目摘要 越来越多的人认识到非酒精性脂肪性肝炎（NASH）是一种流行的肝病， 复杂和异质的潜在原因。现在，新的证据表明，肝硫失调 氨基酸代谢与晚期人NASH相关，并导致脂肪变性显著恶化 和遗传小鼠模型中的损伤。然而，在我们对如何实现这一目标的理解方面存在着重大的知识差距。 含硫氨基酸代谢改变NASH的严重程度，什么机制控制肝脏含硫氨基酸 正常生理代谢和肝脏疾病。这项提议建立在我们发现CoA 代谢是受损的肝含硫氨基酸代谢和肝脂肪之间的关键缺失环节 NASH中的积累和损伤。我们的目标是建立一种新的致病机制， 半胱氨酸（CoA合成底物）的可用性在维持线粒体CoA库以 支持脂肪酸氧化。然而，在晚期NAFLD中，失调的含硫氨基酸通量减少了 半胱氨酸的可用性损害辅酶A的合成。肝脏CoA不足反过来限制了肝脏的能力， 适应增加的脂肪酸流入，创造一种称为代谢能力的条件， 线粒体功能障碍、脂肪变性和氧化应激。从机制上讲，我们已经确定了受损的 甲硫氨酸腺苷转移酶1A（MAT 1A），其驱动上游甲硫氨酸循环转硫通量， 产生半胱氨酸，并过度激活半胱氨酸双加氧酶1型（CDO 1），其介导下游 半胱氨酸消除通过引起半胱氨酸输入和输出不平衡而促成这种致病性病症 在NAFLD。进一步的研究揭示了胆汁酸、TFEB和FGF 15/19信号调节的有趣的串扰 在正常生理条件下，MAT 1A和CDO 1控制肝脏含硫氨基酸和CoA代谢， 纳什我们已经开发了新的小鼠模型，使我们能够操纵肝脏硫氨基酸通量， 两个关键的调节步骤（MAT 1A，CDO 1）。在目标1中，我们将使用肝细胞特异性诱导型CDO 1 转基因小鼠和肝细胞特异性CDO 1敲除小鼠，研究CDO 1表达的改变 胆汁酸信号下游影响肝含硫氨基酸、CoA和GSH代谢，以调节 NASH严重程度。在目标2中，我们将使用肝脏特异性MAT 1A功能获得和功能丧失小鼠模型 确定MAT 1A在调节肝脏含硫氨基酸、CoA和GSH代谢中的意义， 并进一步研究FGF 15/19和TFEB如何调节MAT 1A驱动的硫通量和CoA代谢， 生理学和NASH。通过定义含硫氨基酸代谢与辅酶A代谢的新致病环节， 并描绘了调节肝脏含硫氨基酸和CoA代谢的新机制，我们预计， 这项研究不仅为NASH的发病机制提供了新的见解， 这是一个新的进展，也是开发未来治疗干预的分子基础。