Importance of the Modulation of Glycolysis in the Control of Lactate Metabolism by Fatty Acids in Isolated Hepatocytes from Fed Rats

In liver cells from fed rats, lactate utilization depends on its extracellular concentration and the threshold concentration at which lactate uptake equilibrates release is about 3 mM. Even-chain fatty acids (butyrate, octanoate, or oleate) played a crucial role (i) to depress the lactate release, from 40% (butyrate or oleate) to 72% (octanoate), and (ii) to lower the threshold concentration for lactate utilization (down to 1 mM with octanoate). The effects of fatty acids were connected to their inhibition of hepatic glycolysis, estimated by the detritiation of [6-3H]glucose (about −30% with butyrate or oleate and −45% with octanoate). Fatty acids depressed the cellular concentration of pyruvate which, at physiological concentration of lactate, favors its utilization. The rise in ketone bodies concentration in response to fatty acids reflected an enhanced acetyl CoA production, resulting in an accumulation of citrate. In parallel there was a drop of the cellular concentration of fructose 2,6-biphosphate. As a result, there was an inhibition of the flux through 6-phosphofructo-1 kinase (50, 75, or 40% inhibition with butyrate, octanoate, or oleate, respectively). The other regulatory glycolysis steps, catalyzed by glucokinase and pyruvate kinase, were not affected by fatty acids. Inhibition of hepatic glycolysis by fatty acids seems connected to acetyl-CoA generation since octanoate, readily metabolized to acetyl-CoA and ketone bodies by hepatocytes, had a more potent stimulatory effect on the hepatic uptake of lactate than butyrate or oleate. Propionate, which yields practically no acetyl CoA, slightly stimulated lactate release and elevated the threshold of lactate utilization. The present data suggest thus that, in hepatocytes from fed rats, fatty acids effectively inhibit glycolysis and switch liver cell metabolism toward gluconeogenic conditions, which promotes lactate utilization.