Hepatic urea cycle suppression drives brown fat thermogenesis to counter obesity and liver disease

Abstract

The hepatic urea cycle is consistently suppressed in liver disease and hepatocellular carcinoma (HCC), but whether loss of individual enzymes contributes to disease progression remains unknown. We investigated the role of urea cycle enzyme argininosuccinate synthase 1 (ASS1) in diet- and carcinogen-induced liver disease using hepatocyte-specific deletion of Ass1 in mice. Complete loss of hepatic Ass1 is lethal, but a high-fat diet extends lifespan. Unexpectedly, animals with approximately 85% loss of hepatic Ass1 are markedly protected from diet-induced obesity, liver steatosis, fibrosis, and HCC. Hyperammonemia induced by hepatic Ass1 loss activates brown adipose tissue fatty acid oxidation, driving thermogenesis and increasing energy expenditure. Importantly, targeting Ass1 after obesity onset promotes weight loss and reverses liver steatosis. These findings implicate hepatic ASS1 as a critical regulator of systemic lipid metabolism with therapeutic potential against obesity, liver disease, and HCC.