S8.15 Liver metabolic fluxes in response to high fat diet

Aim Determining adaptations of metabolic fluxes in liver with high fat diet (HF). Methods Glucose, lactate and pyruvate production by perifused hepatocytes isolated from rats fed either a standard or HF diet. Results HF increased gluconeogenesis from glycerol in the presence of octanoate (+ 30%) but decreased it in the absence of fatty acid. This effect was associated with an increase of glycerol metabolism without effect on glycolysis. In both conditions, cytosol was more oxidized whereas mitochondrial compartment was more reduced. Cellular and mitochondrial oxidative capacities were reduced by HF (− 40%). Glycerol metabolism requires a stoichiometric utilization of ATP and NAD + . Therefore depending on the redox condition, control of the pathway is either on the dehydrogenase step, (at low rate of glycerol metabolism), or on the phosphorylation step (high rate of metabolism). Hence, the lower glycerol metabolism observed with HF at high flux is due to diminished oxidative phosphorylation capacity and to an inability to maintain ATP. By contrast, when flux through the pathway is reduced by high redox pressure of fatty acid metabolism, the ability of HF animals to maintain an oxidized cytosolic compartment allows then to metabolize more glycerol. This feature probably results from a higher rate of NADH oxidation via the mitochondrial glycerophosphate dehydrogenase which could be an adaptation to HF for compensating the decrease in oxidative phosphorylation capacity.