Influence of oleate oxidation on pyruvate production and utilization in hepatocytes isolated from fed rats. Effect of 2-[5-(4-chlorophenyl)pentyl]oxiran-2-carboxylate.
Oleate (0.35 and 1.5 mM) decreases, in a concentration-dependent manner, lactate and pyruvate concentrations in hepatocytes, isolated from fed rats, incubated without exogenous substrate. The glycolytic flux, estimated at 18 mM-glucose by [6-3H]-glucose detritiation and apparent production of lactate and pyruvate, is decreased by oleate. The measurement of glycolytic intermediates shows a cross-over at the phosphofructokinase level, which might result from an increased citrate concentration. All those effects are dependent on oleate oxidation in mitochondria, since they are suppressed by 1 microM-2-[5-(4-chlorophenyl)pentyl]oxiran-2-carboxylate (POCA), an inhibitor of the mitochondrial entry of oleate, but not of its uptake by hepatocytes. The decrease of lactate and pyruvate also results from an oleate-induced enhancement of pyruvate utilization by hepatocytes, as shown by the increase of 14CO2 formation from [1-14C]- and [3-14C]-pyruvate, especially at low (0.4 mM) pyruvate concentration. Those oleate effects are also suppressed by POCA. They might be due to an enhanced flux through pyruvate carboxylase and pyruvate dehydrogenase, as a result of an oleate-induced increase in the mitochondrial concentrations of pyruvate and acetyl-CoA. Thus oleate oxidation inhibits production of lactate and pyruvate in fed-rat hepatocytes, as it does in other tissues. But, in the liver, it also enhances the mitochondrial utilization of pyruvate. The physiological implications of those findings are discussed.
D000818:Animals; D004852:Epoxy Compounds / Q000494:pharmacology*; D004988:Ethers, Cyclic / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007773:Lactates / Q000096:biosynthesis / Q000378:metabolism; D019344:Lactic Acid; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D019301:Oleic Acid; D009829:Oleic Acids / Q000378:metabolism* / Q000494:pharmacology; D010084:Oxidation-Reduction; D011773:Pyruvates / Q000096:biosynthesis / Q000378:metabolism*; D019289:Pyruvic Acid; D051381:Rats; D011919:Rats, Inbred Strains
D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D007004:Hypoglycemic Agents; D007773:Lactates; D009829:Oleic Acids; D011773:Pyruvates; D019301:Oleic Acid; D019344:Lactic Acid; C035111:B 807-27; D019289:Pyruvic Acid