NAD+ Supports Metabolism in Impaired Urea Cycle: Preclinical Findings

Synopsis

Problems in the urea cycle and how they relate to obesity and inflammation are not well understood, partly because classical urea cycle defects are severe and dramatic. To study this, researchers made mice lacking the liver enzyme arginase 2 (ARG2), creating a mild urea cycle defect. Early in life, these mice had subtle problems in liver metabolism, mitochondrial function, and TCA cycle activity, but normal energy and glucose levels. By middle age, especially when obese, the mice developed worse glucose and fat problems, which could be improved by restoring NAD+. In humans, blood markers of urea cycle and mitochondrial dysfunction predicted fibroinflammatory liver disease nearly 10 years before diagnosis. These results show that ARG2 links the urea cycle to energy metabolism, and disruptions in this pathway may drive long-term liver disease.

Journal

Cell Metabolism