Sunday, December 22, 2024
12/22/2024
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.
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