Effects of d-3-hydroxybutyrate and acetoacetate on lactate removal in isolated perfused livers from starved and fed rats

Abstract

We examined the influence of nutritional state on the role of the hepatic plasma membrane lactate transporter in determining overall hepatic lactate disposal. The effects of infusion of sodium d-3-hydroxybutyrate (DOHB) on lactate uptake were studied in perfused livers from fed or starved rats. In livers from starved rats, DOHB (15 to 20 mmol/L) inhibited lactate removal by approximately 45%. This effect was associated with a decrease in intracellular lactate concentration, with cell pH remaining unchanged. Inhibition was maximal when perfusate lactate was less than 1.6 mmol/L, and was undetectable at concentrations exceeding 2.5 mmol/L. A similar degree of inhibition was observed with infusion of acetoacetate. These observations add to the evidence that the inhibition of lactate removal by DOHB seen in livers from starved animals is mediated through an effect on the hepatocyte lactate transporter. At similar low levels of perfusate lactate, DOHB infusion produced a decrease in output of lactate from livers obtained from fed animals. When such livers were subjected to prolonged preperfusion, lactate removal, rather than output, was observed; in these livers DOHB stimulated lactate removal, an effect directionally opposite to that observed in livers from starved animals. These data confirm that hepatic lactate transport is a limiting factor for lactate utilization in intact livers from starved rats; in contrast, lactate utilization in livers from fed animals is limited at a step subsequent to plasma membrane transport, ie, possibly pyruvate transport into mitochondria.