Abstract
The metabolism of pyruvate and lactate by rat adipose tissue was studied. Pyruvate and lactate conversion to fatty acids is strongly concentration-dependent. Lactate can be used to an appreciable extent only by adipose tissue from fasted-refed rats. A number of compounds, including glucose, pyruvate, aspartate, propionate, and butyrate, stimulated lactate conversion to fatty acids. Based on studies of incorporation of lactate-2-(3)H and lactate-2-(14)C into fatty acids it was suggested that the transhydrogenation sequence of the "citrate-malate cycle"(1) was not providing all of the NADPH required for fatty acid synthesis from lactate. An alternative pathway for NADPH formation involving the conversion of isocitrate to alpha-ketoglutarate via cytosolic isocitrate dehydrogenase was proposed. Indirect support for this proposal was provided by the rapid labeling of glutamate from lactate-2-(14)C by adipose tissue incubated in vitro, as well as the demonstration that glutamate can be readily metabolized by adipose tissue via reactions localized largely in the cytosol. Furthermore, isolated adipose tissue mitochondria convert alpha-ketoglutarate to malate, or in the presence of added pyruvate, to citrate. Glutamate itself can not be metabolized by these mitochondria, a finding in keeping with the demonstration of negligible levels of NAD-glutamate dehydrogenase activity in adipose tissue mitochondria. Pyruvate stimulated alpha-ketoglutarate and malate conversion to citrate and reduced their oxidation to CO(2). It is proposed that under conditions of excess generation of NADH malate may act as a shuttle carrying reducing equivalents across the mitochondrial membrane. Malate at low concentrations increased pyruvate conversion $$Word$$ citrate and markedly decreased the formation of CO(2) by isolated adipose tissue mitochondria. Malate also stimulated citrate and isocitrate metabolism by these mitochondria, an effect that could be blocked by 2-n-butylmalonate. This potentially important role of malate in the regulation of carbon flow during lipogenesis is underlined by the observation that 2-n-butylmalonate inhibited fatty acid synthesis from pyruvate, but not from glucose and acetate, and decreased the stimulatory effect of pyruvate on acetate conversion to fatty acids.
Highlights
The metabolism of pyruvate and lactate by rat adipose tissue was studied
Pate1 and Hanson [8], using mitochondria isolated from rat adipose tissue, demonstrated that malate synthesized from pyruvate was released by these mitochondria, but at a lower rate than citrate. These findings suggest that malate efflux into the cytosol may provide some of the reducing equivalents it may not account for the total required for lipogenesis
Fasting for hr markedly reduced the rate of fatty acid synthesis from both glucose and pyruvate, whereas increasing the substrate concentration from 0.25 to mM increased lipogenesis so that the rate of fatty acid synthesis found in adipose tissue from fasted animals was comparable to rates found in tissue from the fed animal
Summary
The metabolism of pyruvate and lactate by rat adipose tissue was studied. Isolated adipose tissue mitochondria convert a-ketoglutarate to malate, or in the presence of added pyruvate, to citrate. Pyruvate stimulated a-ketoglutarate and malate conversion to citrate and reduced their oxidation to COZ. Malate at low concentrations increased pyruvate conversion t i citrate and markedly decreased the formation of COz by isolated adipose tissue mitochondria. Malate stimulated citrate and isocitrate metabolism by these mitochondria, an effect that could be blocked by 2-n-butylmalonate This potentially important role of malate in the regulation of carbon flow during lipogenesis is underlined by the observation that 2-n-butylmalonate inhibited fatty acid synthesis from pyruvate, but not from glucose and acetate, and decreased the stimulatory effect of pyruvate on acetate conversion to fatty acids
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