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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

基本信息

批准号：
10343421
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
项目类别：
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/10343421
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 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 base 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

项目摘要

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.

项目总结