Metabolic Complementation between Glucose and Amino Acid Drives Hepatic De Novo Lipogenesis and Steatosis

Increased de novo lipogenesis (DNL) is a hallmark of nonalcoholic fatty liver disease (NAFLD) in obesity, but the macronutrient source for >80% carbon backbone for fatty acid synthesis has not been determined. Here we take an integrated approach to dissect nutrient metabolism, both ex vivo and in vivo. We discover a castling effect of glucose and glutamine metabolism through ex vivo isotope tracing studies that limits the entrance of glucose carbon into the glutamine-dominated tricarboxylic acid cycle (TCA) and DNL pathways. In vivo tracing studies with a high carbohydrate drink (glucose/amino acid, 3:1, w/w) confirm dietary amino acids are twice more efficient than glucose in labeling the hepatic acetyl-CoA and fatty acid pool, and together they account for over 70% of hepatic DNL substrate. Both glucose and glutamine carbon flux into DNL pathways are increased in obese hepatocytes, and metabolic rerouting of substrate carbon toward glycogen synthesis and energy production through GYS2 and GLUD1 overexpression improves hepatic steatosis. Together, these data reveal the quantitative contribution of glucose and amino acid carbon toward hepatic DNL and the development of hepatic steatosis in obesity.