During an overnight fast (12 hour), the liver provides glucose as fuel for other tissues via glycogenolysis and the energetically expensive process of gluconeogenesis. During this period, energy to support this process is generated primarily by the tricarboxylic acid (TCA) cycle. As the duration of fasting prolongs, and glycogen stores are depleted (>24 hour), the liver shifts to the production of ketone bodies that can be used as a secondary fuel source by peripheral tissues. In healthy humans, this period of fasting is generally associated with increased β-oxidation and partitioning of acetyl-CoA away from the TCA cycle and toward ketone body production. We have previously shown that subjects with nonalcoholic fatty liver disease (NAFLD) have increased rates of acetyl-CoA oxidation in the TCA cycle after a 12 hour fast. To examine how NAFLD affects hepatic response to a 24 hour fast, we infused stable isotope tracers into BMI and age matched subjects with (n=12) and without (n=12) NAFLD. At enrollment, NAFLD subjects had greater liver triglycerides (P<0.05) and hepatic insulin resistance (P<0.05), as well as higher fasting plasma concentrations of cholesterol, triglycerides, and glucose (P<0.05). After fasting for 24 hours, subjects with NAFLD failed to suppress endogenous glucose production as compared to controls. This was associated with a higher ratio of plasma insulin to glucagon as well as a blunted increase in the concentration of plasma free fatty acids as fasting duration prolonged. As previously shown in overnight fasted subjects, TCA cycle activity was significantly higher in NAFLD subjects after a 24 hour fast. However, despite elevated TCA cycle flux, NAFLD subjects failed to increase overall β-oxidation compared to controls due to reduced utilization of acetyl-CoA for ketone synthesis.
In conclusion, after a 24 hour fast, the liver of NAFLD subjects produced more glucose and disposed of less fat via β-oxidization by shuttling more acetyl-CoA to the TCA cycle but much less to ketogenesis.
J.A. Fletcher: None. S. Deja: None. S.C. Burgess: None. J. Browning: None.