Argininosuccinate Synthase 1 links hepatic urea cycle to whole body lipid metabolism.

The hepatic urea cycle is consistently suppressed in liver disease and hepatocellular carcinoma (HCC), but whether loss of individual enzymes contributes to disease initiation and progression remains unknown. Using mice with hepatocyte-specific deletion of argininosuccinate synthase 1 (ASS1), the urea cycle enzyme that condenses citrulline and aspartate into argininosuccinate, we investigated the role of ASS1 in diet and carcinogen-induced liver disease progression. We found that complete loss of hepatic Ass1 is lethal, but high fat diet extends lifespan. Unexpectedly, animals with approximately 85% loss of hepatic Ass1 are completed protected from diet-induced obesity, liver steatosis, fibrosis, and HCC. We determined that hepatic Ass1 loss activates fatty acid oxidation in peripheral oxidative tissues leading to increased energy expenditure and protection from disease phenotypes. Moreover, targeting Ass1 after obesity onset promotes weight loss and reverses liver steatosis. These findings implicate hepatic ASS1 as a novel regulator of whole-body lipid metabolism that can be targeted to prevent obesity, liver disease, and HCC.