Fatty liver disrupts glycerol metabolism in gluconeogenic and lipogenic pathways in humans

It is a challenge to assess metabolic dysregulation in fatty liver of human patients prior to clinical manifestations. Here, we recruited obese, but otherwise healthy, subjects to examine biochemical processes in the liver with simple triglyceride accumulation using stable isotopes and NMR analysis of metabolic products in blood. Intrahepatic triglycerides were measured using ¹ H magnetic resonance spectroscopy, and volunteers received ² H ₂ O and [U- ¹³ C ₃ ] glycerol orally, followed by a series of blood draws. NMR analysis of plasma triglycerides and glucose provided detailed information about metabolic pathways in patients with simple hepatic steatosis. Compared with subjects with low hepatic fat, patients with hepatic steatosis were characterized by the following: lower ¹³ C enrichments in the glycerol backbones of triglycerides (i.e., TG-[ ¹³ C]glycerol), higher [U- ¹³ C ₃ ] glycerol metabolism through the tricarboxylic acid (TCA) cycle, delayed gluconeogenesis from [U- ¹³ C ₃ ]glycerol, and less flexibility in adjusting supporting fluxes of glucose production upon an oral load of glycerol. In summary, simple hepatic steatosis was associated with enhanced [U- ¹³ C ₃ ] glycerol metabolism through pathways that intersect the TCA cycle and delayed gluconeogenesis from glycerol.