The Stimulation of Hepatic Gluconeogenesis by Acetoacetate Precursors A ROLE FOR THE MONOCARBOXYLATE TRANSLOCATOR*

The regulation of the gluconeogenic pathway from the 3-carbon precursors pyruvate, lactate, and alanine was investigated in the isolated perfused rat liver. Using pyruvate (<1 mM), lactate, or alanine as the gluconeogenic precursor, infusion of the acetoacetate precursors oleate, acetate, or p-hydroxybutyrate stim- ulated the rate of glucose production and, in the case of pyruvate (<1 mM), the rate of pyruvate decarbox- ylation. a-Cyanocinnamate, an inhibitor of the monocarboxylate transporter, prevented the stimulation of pyruvate decarboxylation and glucose production due to acetate infusion. With lactate as the gluconeogenic precursor, acetate infusion in the presence of L-carni-tine stimulated the rate of gluconeogenesis (100%) and ketogenesis (60%) without altering the tissue acetyl-CoA level usually considered a requisite for the stim- ulation of gluconeogenesis by fatty acids. Hence, our studies suggest that gluconeogenesis from pyruvate or other substrates which are converted to pyruvate prior to glucose synthesis may be limited or controlled by the rate of entry of pyruvate into the mitochondrial compartment on the monocarboxylate translocator. The rate of pyruvate decarboxylation in the isolated perfused rat liver is stimulated by infusion of precursors of acetoacetate provided that the perfusate pyruvate

carboxylate transporter, prevented the stimulation of pyruvate decarboxylation and glucose production due to acetate infusion. With lactate as the gluconeogenic precursor, acetate infusion in the presence of L-carnitine stimulated the rate of gluconeogenesis (100%) and ketogenesis (60%) without altering the tissue acetyl-CoA level usually considered a requisite for the stimulation of gluconeogenesis by fatty acids. Hence, our studies suggest that gluconeogenesis from pyruvate or other substrates which are converted to pyruvate prior to glucose synthesis may be limited or controlled by the rate of entry of pyruvate into the mitochondrial compartment on the monocarboxylate translocator.
The rate of pyruvate decarboxylation in the isolated perfused rat liver is stimulated by infusion of precursors of acetoacetate provided that the perfusate pyruvate concentration is less than 1 mM (1-4). It has been our contention that at low (probably physiological) concentrations of pyruvate, a situation in which nearly all of the pyruvate transport across the mitochondrial membrane occurs via the monocarboxylate transporter, intramitochondrially generated acetoacetate may effectively replace hydroxyl ions as the counter ion for pyruvate transport on the monocarboxylate translocator. Acetoacetate has been shown to be transported in exchange for pyruvate via the monocarboxylate translocator in mitochondrial systems (5,6). It has been demonstrated that the rates of pyruvate transport and pyruvate decarboxylation are stimulated in the presence of an acetoacetate precursor in isolated rat liver mitochondria (2). Furthermore, the decarboxylation of the branched chain a-keto acid, a-ketoisovalerate, which is transported across the mitochondrial membrane via the monocarboxylate translocator (7), is accelerated by 0-hydroxybutyrate and acetate, both precursors of mitochondrial acetoacetate (8)(9)(10). Stimulation of the rate of entry of monocarboxylates such as pyruvate into the mitochondrial compartment due to exchange with mitochondrially generated acetoacetate results in an elevated mitochondrial concentration of the imported substrate. Hence, the rate of decarboxylation of pyruvate is stimulated both by mass action and the inhibitory effect of pyruvate on the pyruvate dehydrogenase kinase, resulting in the interconversion of the enzyme complex to the active, dephospho-form (3).
If our hypothesis is correct concerning the relationship between mitochondrial pyruvate uptake and acetoacetate efflux, other metabolic processes such as gluconeogenesis which depend upon pyruvate import into the mitochondrial compartment should be affected. While the published data are not conclusive, it has been suggested (11-13) that glucagon and &butyryl cyclic AMP stimulate the operation of the mitochondrial monocarboxylate translocase, leading to a stimulation of hepatic gluconeogenesis.
The present study was performed to ascertain whether the rate of gluconeogenesis from pyruvate or its precursors is increased under metabolic conditions in which acetoacetate precursors stimulate the rate of decarboxylation of these same substrates. In effect, we have employed the decarboxylation of [l-14C]pyruvate as a probe of the monocarboxylate transport system in the perfused rat liver in order to characterize the regulatory significance of precursor translocation in the gluconeogenic process.

MATERIALS AND METHODS
Male Sprague-Dawley rats (180-200 g) were used for all experiments. Animals were fasted for a 24-h period prior to surgical removal of the liver under pentobarbital anesthesia. A noncirculating liver perfusion technique using a hemoglobin-free perfusion medium was employed (14). The perfusion medium was Krebs-Henseleit bicarbonate buffer, pH 7.4, equilibrated with a mixture of oxygen to carbon dioxide (95:5%) and was maintained at 37 "C. Substrates were infused into the perfusion system immediately prior to the liver. Samples of the effluent perfusate were collected at 30-s intervals for metabolite analyses. Aliquots (2.5 ml) of the perfusate were placed in 25-ml Erlenmeyer flasks sealed with rubber serum stoppers equipped with plastic center wells (both obtained from Kontes Glass, Vineland, NJ) containing 0.3 ml of phenylethylamine. Labeled Cot from the perfusate samples was released by injecting 0.5 ml of 1 N HCl into the flasks followed by gentle agitation for 1 h. The center wells were transferred to scintillation vials containing 10 ml of Aquasol (New England Nuclear) and counted. Knowing the quench correction and the specific radioactivity of the 1-'%-labeled pyruvate, the metabolic flux through the pyruvate dehydrogenase complex was estimated (10).
Glucose in the perfusate samples was measured using the method of Bergmeyer et al. (15). Ketone bodies acetoacetate and P-hydroxybutyrate were measured by the procedures of Mellanby and Williamson (16) and Williamson and Corkey (17), respectively. Lactate and pyruvate in perfusate samples were determined according to the 7525 procedures of Gutmann and Wahlefeld (18) and Passonneau and Lowry (19), respectively.
For each experiment, glucose production by the liver was measured in the presence and absence of various precursors in the perfusion medium. The rate of glucose output by the liver was corrected for endogenous glucose production, e.g. the rate in the absence of any gluconeogenic precursors. In this series of experiments, the endogenous rate of glucose output was 4.8 +. 0.5 (n = 15) pmo1.g". h-'.
Glucose production rates in the effluent perfusate were measured either at 1-min intervals or under the various steady state conditions indicated in the individual figures. Coenzyme A and various acyl-CoA derivatives were measured in neutralized perchloric acid extracts of freeze-clamped perfused livers using the high performance liquid chromatographic procedure described by DeBuysere and Olson (20).
Aquasol and phenylethylamine were obtained from New England Nuclear. [l-14C]Pyruvate was purchased from Amersham Corp. Glucose-6-phosphate dehydrogenase, hexokinase, and pyruvate were obtained from Boehringer Mannheim. Sodium acetate was obtained from Fisher. All other chemicals were of the highest purity available commercially.

RESULTS
As the perfusate pyruvate concentration is increased in a stepwise fashion in an isolated, perfused rat liver from a fasted rat, the rates of both pyruvate decarboxylation and glucose production increase in a parallel fashion as demonstrated in Fig. 1. Maximal rates of glucose output and pyruvate decarboxylation were approached only after the perfusate pyruvate concentration exceeded 20 mM. Experiments performed using livers from fed rats indicated that pyruvate decarboxylation was maximal at perfusate pyruvate concentrations of 10 mM (1).
As a starting point for our investigation of the effects of acetoacetate precursors on the supply of gluconeogenic precursors, oleate was infused into a rat liver perfused with 0.5 mM [l-14C]pyruvate (Fig. 2). Oleate addition resulted in a stimulation of the rates of [ l-14C]pyruvate decarboxylation and glucose production by 33 and 120%, respectively. Concomitant with the changes in glucose production and pyruvate decarboxylation, the rate of ketogenesis was stimulated 5.5fold, and the mitochondrial oxidation-reduction state, as measured by [P-hydroxybutyrate]/[acetoacetate] ratio, increased from 0.125 in the absence of oleate to 0.37 upon oleate addition (Fig. 2). Oleate also stimulated the rate of glucose production in livers presented with gluconeogenic precursors L-lactate (180%) and L-alanine (165%) ( Table I)  tion-reduction state during oleate infusion in livers perfused with either lactate or alanine were similar to those observed with pyruvate as the gluconeogenic precursor. The effect of infusing alternative acetoacetate precursors, acetate and P-hydroxybutyrate, on the rates of pyruvate decarboxylation and glucose production in livers from fasted rats is illustrated in Fig. 3. Acetate and 8-hydroxybhtyrate infusion caused nearly identical stimulatory effects on pyruvate decarboxylation, and both acetoacetate precursors nearly doubled the rate of glucose production (e.g. see the metabolite rates at the top of Fig. 3). It should be noted that during both 8-hydroxybutyrate (Fig. 3) and oleate ( Fig. 2) infusion, the oxidation-reduction state of the mitochondrial NADH/NAD+ couple was shifted towards the reduced state which is inconsistent with the observed stimulation of the metabolic flux through the pyruvate dehydrogenase complex.
The data presented in Fig. 4 demonstrate that the acceleration of gluconeogenesis in the fasted rat liver by acetoacetate precursors was not observed only when pyruvate was the gluconeogenic precursor. Both acetate and P-hydroxybutyrate infusion more than doubled the rate of glucose production using lactate (20 mM) as the gluconeogenic precursor. When alanine (10 mM) was employed as the gluconeogenic precursor, acetate infusion caused a 60% stimulation of glucose production, while 0-hydroxybutyrate increased glucose production by more than 2-fold (data not shown). Additionally, both acetate and P-hydroxybutyrate infusion caused a diminution of the sum of lactate plus pyruvate in the effluent perfusate of livers perfused with alanine as the gluconeogenic precursor (data also not shown).
The stimulation of the metabolic flux through the pyruvate dehydrogenase reaction by acetoacetate precursors is accompanied by an increase in the activation state of the multienzyme complex ( i e . active pyruvate dehydrogenase/total pyruvate dehydrogenase) (3). Furthermore, we have demonstrated that inhibition of the pyruvate dehydrogenase kinase/ phosphatase interconversion system, by dichloroacetate for

The effect of oleate infusion on the rate of glucose production in a liver from a 24-h fasted rat perfused with either 20 mM L-lactate or 10 mM L-alanine
The perfusion experiments were conducted exactly as illustrated for pyruvate in Fig. 2 except that 20 mM Llactate or 10 RIM L-alanine replaced 0.5 mM pyruvate. The rates of glucose production, ketogenesis, and lactate and pyruvate production were measured in the perfusate samples collected under steady state conditions, Le. between 7 and 10 min after initiation of the various substrate infusions. Glucose production rates were corrected for endogenous rates of glucose output from the livers in the absence of any exogenously added substrates. Each value is a mean f S.D. of at least five determinations.

Condition
Glucose @-Hydroxy-  Effect of acetate and DL-b-hydroxybutyrate on the rates of pyruvate decarboxylation and glucose production in isolated perfused rat livers from 24-h fasted rats. In separate experiments, livers were perfused with 0.5 mM [l-"C]pyruvate and acetate or p-hydroxybutyrate was co-infused for 10-min periods indicated by horizontal bars. Perfusate samples were analyzed for "COZ production, glucose production, and ketone bodies as described under "Materials and Methods." Glucose production rates were corrected for endogenous glucose production from the liver in the absence of any exogenous substrates. example, prevents the stimulation of pyruvate decarboxylation by acetoacetate precursors (1,3,8). In order to assess the effects of acetate on glucose production in a rat liver perfused In separate experiments, livers perfused with 20 mM L-lactate were exposed to acetate or 8-hydroxybutyrate infusion for 10-min intervals indicated by the horizontal bars. The rates of glucose and ketone body production were measured in effluent perfusate samples as described under "Materials and Methods." with a low pyruvate concentration in which the pyruvate dehydrogenase complex was maximally active, dichloroacetate, a potent inhibitor of the pyruvate dehydrogenase kinase (21), was employed to allow the interconversion of nearly all of the enzyme complex to the active dephospho-form. When dichloroacetate was infused into a liver perfused with 0.5 mM pyruvate, the rate of pyruvate decarboxylation was stimulated by 45% over control rates. The rate of glucose production from pyruvate was not affected significantly by dichloroacetate infusion. Addition of acetate in the presence of dichloroacetate resulted in an acceleration of the rate of glucose production by 25% (results not shown).
Moreover, when livers were perfused with high perfusate pyruvate concentrations (e.g. 5 mM), acetate infusion into the liver did not affect either the rate of pyruvate decarboxylation or the rate of glucose production (data not shown). Under these perfusion conditions, pyruvate transport via the monocarboxylate translocator was not in any way rate-limiting, and the pyruvate dehydrogenase enzyme complex was largely (80%) converted to its active form.
In order to demonstrate the involvement of the mitochondrial monocarboxylate translocator in the stimulation of glucose production during infusion of acetoacetate precursors into livers perfused at low (e.g. <1 mM) pyruvate concentrations, a-cyanocinnamate, an inhibitor of the mitochondrial monocarboxylate translocator, was infused to inhibit the transport of pyruvate across the mitochondrial membrane (3) (Fig. 5). In the presence of a-cyanocinnamate, infusion of [l-14C]pyruvate at 5 mM resulted in a rate of pyruvate decarboxylation equivalent to that observed with 0.5 mM pyruvate in the absence of a-cyanocinnamate (e.g. see Fig. 3). Since acyanocinnamate (3 mM) inhibits the mitochondrial monocarboxylate translocator in excess of 95% (3), it was inferred that the intramitochondrial pyruvate concentration due mainly to passive diffusion of pyruvate (5 mM) in the perfusion medium across the mitochondrial membrane in the presence of a-cyanocinnamate was equivalent to that observed in the absence of the inhibitor at a perfusate pyruvate concentration of 0.5 mM. Upon acetate addition, the rate of ketogenesis was elevated, but the mitochondrial oxidation-reduction state as measured by the [P-hydroxybutyrate]/[acetoacetate] ratio in the effluent perfusate was unaffected. In spite of the stimulated rate of ketogenesis during acetate infusion, acyanocinnamate prevented a significant perturbation in the The effect of acetate on the rates of pyruvate decarboxylation and glucose and ketone body production in the presence of a-cyanocinnamate in perfused livers from a 24-h fasted rat. The liver was perfused for 10 min with a-cyanocinnamate prior to initiation of pyruvate infusion. Acetate was infused for a 10min period indicated by the horizontal bar. l4COZ production and glucose and ketone body production in perfusate samples were measured as described under "Materials and Methods." Glucose production rates were corrected for endogenous rates of glucose production.

FIG. 6. The effect of b-hydroxybutyrate and acetate on the rates of glucose production from lactate in the presence of Lcarnitine in perfused livers derived from 24-h fasted rats.
The various compounds were infused into the livers for time periods indicated by horizontal bars. Effluent perfusate samples were assayed for glucose and ketone bodies, p-hydroxybutyrate and acetoacetate, as described under "Materials and Methods." Glucose production rates were corrected for endogenous rates of glucose production in the absence of lactate. rates of either pyruvate decarboxylation or glucose production.
It must be noted that the conventional, generally accepted mechanism for explaining stimulatory effects of ketogenic substrates such as acetate, P-hydroxybutyrate, and oleate on the rate of hepatic gluconeogenesis is through an elevation of mitochondrial acetyl-coA levels which should activate the pyruvate carboxylase reaction (for review see Ref. 22). The experiments depicted in Fig. 6 and Table I T were performed in an attempt to minimize the potential contribution of the mitochondrial acetyl-coA level to the gluconeogenic increase observed upon acetate and B-hydroxybutyrate infusion. Following stabilization of the rate of glucose production from lactate (20 mM), infusion of L-carnitine (20 mM) resulted in a modest stimulation of glucose production (40%) and an increase in the rate of acetoacetate production (34%). Infusion of DL-P-hydroxybutyrate (20 mM; Fig. 6, closed circles) in the presence of L-carnitine stimulated the rates of glucose and acetoacetate production by 2-and 11-fold, respectively. Similarly, acetate infusion (10 mM; Fig. 6, open circles) into livers perfused with lactate and L-carnitine stimulated the rates of glucose and acetoacetate production by 120 and 30%, respectively. Measurements of free CoASH and various appropriate acyl-CoA derivatives in extracts of perfused livers freezeclamped under various steady state perfusion conditions described in Figs. 3 and 6 are tabulated in Table 11. Infusion of P-hydroxybutyrate, oleate, or acetate into livers perfused with lactate increased tissue acetyl-coA levels by 80, 70, and 22%, respectively, compared to control livers perfused in the presence of lactate alone. Inclusion of L-carnitine (a) reduced significantly the increase in tissue acetyl-coA when P-hydroxybutyrate was the added acetoacetate precursor and (b) prevented completely the elevation of the acetyl-coA level when acetate was infused. Hence, in the absence of a measurable change in the tissue acetyl-coA level, acetate infusion

Tissue levels for coenzyme A derivatives in rat livers perfused with various ketogenic substrates which stimulate gluconeogenesis from lactate
Livers from fasted rats were perfused under the conditions indicated. The livers were freeze-clamped at the times indicated, and perchloric acid extracts of these livers were analyzed for various acyl-CoA derivatives as described under "Methods and Materials." Each value is a mean value & S.D. caused nearly a doubling of the rate of glucose output by the liver (Fig. 6).

DISCUSSION
The present study was an attempt to provide an experimental basis for our suggestion that the translocation of monocarboxylate gluconeogenic precursors across the mitochondrial membrane may be a regulatory site in the gluconeogenic process. It is our suggestion that at low, probably physiological intracellular pyruvate concentrations, when most or all of the pyruvate transport across the mitochondrial membrane occurs via the monocarboxylate translocator (7, 24), intramitochondrially generated acetoacetate exchanges for cytosolic pyruvate, resulting in an elevation of the intramitochondrial pyruvate concentration (2). An increase in the mitochondrial pyruvate concentration increases the metabolic flux through the pyruvate dehydrogenase reaction by mass action, and because pyruvate is an effective inhibitor of the pyruvate dehydrogenase kinase (23), an activation of the pyruvate dehydrogenase complex is effected (1-4, 8). If the mitochondrial pyruvate concentration is increased during a period of rapid ketogenic efflux, the rate of the pyruvate carboxylase reaction and, subsequently, the gluconeogenic pathway should be enhanced. This thesis was approached experimentally in the present study.
With pyruvate as the gluconeogenic substrate, the rate of glucose production was not maximal even when the perfusate pyruvate concentration was raised to 20 mM, indicating that the apparent K,,, for glucose production from pyruvate was in the millimolar range (Fig. 1). Additionally, our finding that the rate of pyruvate decarboxylation with varying perfusate pyruvate concentrations in the 24-h fasted rat was not saturated at 20 mM and the fact that pyruvate decarboxylation in the fed rat is at its maximum a t 10 mM (1) indicate a difference in the regulatory characteristics of the pyruvate dehydrogenase system in these two metabolic situations. As demonstrated for the pyruvate dehydrogenase complex in heart mitochondria derived from fed and fasted rats (25, 26), this difference may be a consequence of decreased inhibition of the pyruvate dehydrogenase kinase by pyruvate in fasted rat livers. Since acetyl-coA and NADH stimulate the pyruvate dehydrogenase kinase (27,28) and pyruvate is an inhibitor of the kinase, it follows that in the fasted rat liver higher concentrations of pyruvate may be required to inhibit the kinase in the face of elevated acetyl-CoA/CoASH and NADH/NAD+ ratios. The present study indicates that all mitochondrial acetoacetate precursors, e.g. oleate, acetate, and P-hydroxybutyrate, increase the rate of glucose production by the rat liver at low ( 4 mM) perfusate pyruvate concentrations. At higher concentrations of pyruvate in the perfusion medium, which must be considered nonphysiological, acetate infusion affected neither the rate of glucose production nor the rate of pyruvate decarboxylation. This finding is consistent with our view that a t lower pyruvate concentrations the bulk of the pyruvate is transported into the mitochondrial matrix via the monocarboxylate translocator (7, 24). A rapid acceleration in the rate of acetoacetate generation causes an increase in the net exchange of pyruvate for acetoacetate across the monocarboxylate transporter and the attendant stimulation of both pyruvate decarboxylation and carboxylation (i.e. gluconeogenesis). Studies with gluconeogenic precursors other than pyruvate, i e . lactate and alanine, which first must be converted to pyruvate in the gluconeogenic pathway, demonstrated that all acetoacetate precursors (i.e. oleate, acetate, and &hydroxybutyrate) stimulated the rate of glucose production in 24-h fasted rat livers irrespective of the gluconeogenic precursor infused.
An alternative interpretation of the oleate-and acetatemediated stimulation of gluconeogenesis in fasted rat livers perfused with low pyruvate concentrations, lactate or alanine, could be that elevated mitochondrial acetyl-coA levels resulting from oleate oxidation or acetate activation (Table 11) may stimulate the pyruvate carboxylase reaction, thereby enhancing the rate of glucose production (see Ref. 22 for review).
Recently, it has been demonstrated that D-P-hydroxybutyrate may be converted to acetoacetate in mitochondria followed by a slower conversion of acetyl-coA in the cytosol for lipogenesis (29). However, in livers of fasted rats, a condition during which lipogenesis is minimal, cytosolic acetyl-coA generation from P-hydroxybutyrate should be expected to be insignificant. Similarly, the conversion of L-P-hydroxybutyrate to intramitochondrial acetyl-coA also has been shown to be minimal in livers from fasted rats (30). The elevated acetyl-CoA levels observed in freeze-clamped livers during infusion of DL-P-hydroxybutyrate (Table 11) are most probably a consequence of decreased tricarboxylic acid cycle flux due to an elevated mitochondrial NADH/NAD+ ratio resulting from phydroxybutyrate conversion to acetoacetate.
It is our contention that the stimulation of hepatic gluconeogenesis from %carbon precursors by ketogenic substrates may not be solely a result of an increased mitochondrial acetyl-coA level acting to stimulate pyruvate carboxylation. First, acetate stimulates hepatic glucose production neither in livers perfused at high pyruvate concentrations nor in livers perfused with the monocarboxylate transport inhibitor acyanocinnamate. Second, in livers perfused with lactate, infusion of L-carnitine resulted in a 40% stimulation in the rate of glucose production (Fig. 6) despite a slight decrease in the tissue acetyl-coA level (Table 11). However, the rate of acetoacetate production was stimulated probably due to an increase in the rate of oxidation of endogenous fatty acids facilitated by the L-carnitine infusion. Finally, infusion of acetate in livers perfused with lactate plus L-carnitine stimulated the rate of glucose production by 2-fold in the absence of a significant change in the tissue acetyl-coA level. Again, under these metabolic conditions, the rate of acetoacetate production was increased over comparable control values, i.e. in the presence of lactate and L-carnitine.
Similarly, for reasons indicated below, we would like to note that the stimulation of gluconeogenesis observed during Phydroxybutyrate infusion in livers was not solely a reflection of altered mitochondrial and, consequently, the cytosolic oxidation-reduction state. First, in livers perfused with 20 mM lactate, a condition under which the cytosolic NADH/NAD+ oxidation-reduction couple is already in a highly reduced state, infusion of P-hydroxybutyrate stimulated the rate of glucose production (Fig. 4). Second, P-hydroxybutyrate infusion in a liver from a 24-h fasted rat perfused with high pyruvate levels caused no change in glucose output (results not shown), while the rate of pyruvate decarboxylation was inhibited significantly (3), presumably as a result of an increased reduction of the mitochondrial redox state. Finally, infusion of either acetate or B-hydroxybutyrate stimulated gluconeogenesis to a similar extent using either pyruvate or lactate as the gluconeogenic precursors. It should be noted that acetate metabolism in the perfused rat liver does not affect the mitochondrial or the cytosolic NADH/NAD+ ratio as measured by the ratios of @-hydroxybutyratelacetoacetate and lactate/pyruvate, respectively, in the effluent perfusate.
One of the requisites for observing the stimulation of pyruvate decarboxylation by acetoacetate precursors is that the pyruvate dehydrogenase kinase/phosphatase interconversion system must not be inhibited. Hence, in the presence of dichloroacetate, an inhibitor of the pyruvate dehydrogenase kinase, the rate of pyruvate decarboxylation was not stimulated by acetoacetate precursors (data not shown). Any resultant alteration (e.g. increase) in the intramitochondrial pyruvate concentration caused by an accelerated pyruvate transport should have no effect on the interconversion system in the presence of dichloroacetate. However, the rate of glucose output by the liver in the presence of dichloroacetate was increased by acetate co-infusion as would be expected if the acetoacetate generated from acetate caused an enhanced exchange of pyruvate for acetoacetate.
Finally, the demonstration that inhibition of the monocarboxylate translocator by a-cyanocinnamate prevents the stimulation of both pyruvate decarboxylation and glucose production from pyruvate again is consistent with our proposition that a functional monocarboxylate transporter is necessary to observe the putative acetoacetate/pyruvate exchange transport process with the attendant acceleration of gluconeogenesis.
The implications of the suggested relationship between the ketogenic process and the gluconeogenic pathway are obvious. Under metabolic conditions, e.g. diabetes or prolonged fasting, resulting in accelerated hepatic fatty acid oxidation and a rapid ketogenic rate, gluconeogenesis from 3-carbon precursors is usually stimulated. The proposed facilitation of the rate of glucose synthesis at the level of the transport of pyruvate into the mitochondrial compartment may be considered one of a variety of regulatory alterations involved in accelerating the gluconeogenic pathway under physiological conditions.