3-Mercaptopicolinic acid, an inhibitor of gluconeogenesis

DiTullio, Nicholas W.; Berkoff, Charles E.; Blank, Benjamin; Kostos, Vincent; Stack, E J; Saunders, Harry L.

doi:10.1042/bj1380387

Cited by 177 publications

(76 citation statements)

References 15 publications

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“…As shown in Table 1, in periportal hepatocytes (in which glutamine synthetase activity was less than 10% of total hepatocyte glutamine synthetase activity) stimulation of glycogen synthesis by alanine, proline and asparagine was as observed in total hepatocyte preparations [I] (see also below) and was further enhanced by the presence of 3-mercaptopicolinic acid, an inhibitor of phosphoenolpyruvate carboxykinase [17], which is in agreement with similar observations in total hepatocyte preparations [I, 41.…”

Section: Resultssupporting

confidence: 77%

Stimulation of glycogen synthesis in hepatocytes by added amino acids is related to the total intracellular content of amino acids

Plomp¹,

Boon²,

P.³

et al. 1990

European Journal of Biochemistry

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Katz et al. [Katz, J.,Golden, S. & Wals, P. A. (1976) Proc. Not1 Acud. Sci. USA 73, 3433-34371 were the first to report that in hepatocytes isolated from fasted rats and incubated with either dihydroxyacetone, glucose or other sugars, glycogen synthesis was greatly accelerated by addition of amino acids. We have looked for possible mediators responsible for this effect and have tested the effect of alanine, proline, asparagine, glutamine or a combination of ammonia with either pyruvate or lactate in activating glycogen synthesis from dihydroxyacetone. The following observations were made.1. Stimulation of glycogen synthesis by alanine, proline or asparagine does not require production of glutamine since the effect also occurs in periportal hepatocytes which lack glutamine synthetase.2. Under various conditions, stimulation of glycogen synthesis by added amino acids directly correlated with increases in the intracellular content of amino acids, expressed in osmotic equivalents.3. 3-Mercaptopicolinic acid, the inhibitor of phosphoenolpyruvate carboxykinase, further enhances stimulation of glycogen synthesis by amino acids because it increases the intracellular accumulation of aspartate and glutamate.4 It is concluded that activation of glycogen synthesis by added amino acids is due to an increase in intracellular osmolarity following their uptake and the accumulation of intracellular catabolites. This results in an increase in hepatic volume which stimulates glycogen synthesis [Baquet, A., Hue, L., Meijer, A. J., van Woerkom, G. M. & Plomp, P. J. A. M. (1990) J. Biol. Chem. 265, 955-9591, In 1976 Katz et al. [l] showed that, in hepatocytes fromIn none of the studies mentioned above were intracellular fasted rats, addition of amino acids like glutamine, alanine or metabolites measured as a means of obtaining information on asparagine greatly accelerated glycogen synthesis from the mechanism by mcans of which amino acids stimulate physiological concentrations of glucose (and other precursors, glycogen synthesis. Such an analysis is described in this paper. such as fructose, sorbitol or dihydroxyacetone); only in the presence of amino acids were rates of glycogen synthesis comparable to those found in vivo after the fasted/refed transition. In order to obtain appreciable rates of glycogen synthesis in MATERIALS AND METHODS the absence of amino acids, either very high concentrations of glucose must be added [2] or N a + in the incubation medium must be replaced by K + [3].The mechanism underlying the stimulation of glycogen synthesis by amino acids is still not understood [4-81. Several compounds have been proposed as possible candidates involved in this stimulation, ranging from an unknown catabolite of glutamine, alanine or asparagine [l], added amino acids themselves [7], carbamoyl phosphate [6] to glutamine [8]. Chen and Lardy [5] found that leucine reinforced the stimulation of glycogen synthesis by glutamine. Since stimulation of glycogen synthesis by glutamine plus leucine was cycloheximide-sensitive, they ...

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Section: Resultssupporting

confidence: 77%

Stimulation of glycogen synthesis in hepatocytes by added amino acids is related to the total intracellular content of amino acids

Plomp¹,

Boon²,

P.³

et al. 1990

European Journal of Biochemistry

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“…The concentration of glycerol 1 -phosphate increased rapidly to reach a peak level within 6 min whereas that of fructose 2,6-bisphosphate decreased more slowly over a period of about 10 min. We also observed that the gluconeogenic inhibitor, 3-mercaptopicolinate [35], reduced the accumulation of glycerol 1-phosphate by about 50% but had no effect on fructose 2,6-bisphosphate levels.…”

Section: Fructose 26-bisphosphate Concentration and Glycolytic Fluxmentioning

confidence: 58%

The capacity of reducing‐equivalent shuttles limits glycolysis during ethanol oxidation

Berry

Gregory

Grivell

et al. 1994

European Journal of Biochemistry

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The inhibition of glycolysis during ethanol oxidation has been examined in isolated hepatocytes from fasted rats. Glycolytic flux was measured by determining the rate of release of tritium from [6-3H]glucose. During ethanol oxidation, the rate of glycolysis was inhibited 80% in freshly prepared hepatocytes, in which shuttle intermediates are depleted, but was depressed only about 20% in the presence of asparagine, a condition under which activity of the malate/aspartate shuttle was restored to normal levels. The inhibition of glycolysis was also partially released by addition of pyruvate and when alcohol dehydrogenase activity was depressed by 4-methylpyrazole. Titrations with this inhibitor revealed inverse linear relationships between the rates of glycolysis and ethanol oxidation. For any given rate of ethanol oxidation, glycolytic flux was lowest and the [lactate]/[pyruvate] ratio highest in the presence of aminooxyacetate, an inhibitor of the malatelaspartate shuttle, whereas flux was highest and the ratio lowest in the presence of asparagine. During these titrations with 4-methylpyrazole the inhibition of ethanol oxidation and concomitant restoration of glycolysis were accompanied by a decline in the [lactate]/[pyruvate] ratio, a substantial fall in the rate of reducingequivalent transfer from cytoplasm to mitochondria and an increase in lactate accumulation. These findings imply that the reducing equivalents generated during ethanol oxidation compete with those arising in glycolysis for transfer to the mitochondria. This competition leads to an inhibition of aerobic glycolysis, and at the same time contributes to a rise in cytoplasmic NADH and fall in NAD+ that results in depression of anaerobic glycolysis. Allosteric inhibition of 6-phosphofructo-1-kinase due to a decrease in the concentration of fructose 2,6-bisphosphate did not appear to play a primary role in the inhibition of glycolysis by ethanol. Ethanol oxidation had no effect on glucose phosphorylation as measured with [2-3H]glucose, but induced a substantial increase in cycling between glucose and glucose 6-phosphate.Although the depression of glycolysis associated with ethanol oxidation was reported 20 years ago [l], there remains some uncertainty as to the mechanism of ethanol action [l -41. The prevailing view is that ethanol oxidation brings about an inhibition of glyceraldehyde-3-phosphate dehydrogenase activity, due either to a limitation in the availability of NAD+ or to a direct inhibitory effect of NADH on the enzyme [l, 4, 51. The fall in NAD' and concomitant rise in NADH is considered to be a consequence of the accumulation of reducing equivalents in the cytoplasm as a result of Enzymes. 6-Phosphofructo-1-kinase (EC 2.7

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“…For the insulin tolerance test, nonfasted mice were injected intraperitoneally with human regular insulin (0.75 U/kg). For the pyruvate challenge test, mice deprived of food for 16 hours were injected intraperitoneally with pyruvate dissolved in saline (2 g/kg); where indicated, 3-mercaptopicolinic acid (3-MPA; 30 mg/kg), an inhibitor of gluconeogenesis (21,22), was administered orally 30 minutes before the test. The 3-MPA was synthesized as described (23).…”

Section: Methodsmentioning

confidence: 99%

Hyperinsulinemia, glucose intolerance, and dyslipidemia induced by acute inhibition of phosphoinositide 3-kinase signaling in the liver

Miyake¹,

Ogawa²,

Matsumoto³

et al. 2002

J. Clin. Invest.

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3-Mercaptopicolinic acid, an inhibitor of gluconeogenesis

Cited by 177 publications

References 15 publications

Stimulation of glycogen synthesis in hepatocytes by added amino acids is related to the total intracellular content of amino acids

Stimulation of glycogen synthesis in hepatocytes by added amino acids is related to the total intracellular content of amino acids

The capacity of reducing‐equivalent shuttles limits glycolysis during ethanol oxidation

Hyperinsulinemia, glucose intolerance, and dyslipidemia induced by acute inhibition of phosphoinositide 3-kinase signaling in the liver

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