A Novel mechanism for inhibition of β‐oxidation by methylenecyclopropylacetyl‐CoA, a metabolite of hypoglycin

Osmundsen, Harald; Sherratt, H. S. A.

doi:10.1016/0014-5793(75)80951-3

Cited by 90 publications

(31 citation statements)

References 18 publications

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“…The hypoglycin metabolite methylenecyclopropylacetyl-CoA selectively inhibits butyryl-CoA dehydrogenase (EC 1.3.99.2), while palmitoyl-CoA dehydrogenase is not inhibited [14,15]. It was therefore of interest to study the effect of blocked butyryl-CoA dehydrogenase on pent-4-enoylcarnitinedependent acyl-CoA fluxes.…”

Section: Resultsmentioning

confidence: 99%

Effects of pent‐4‐enoate on flux through acyl‐CoA dehydrogenases of β‐oxidation in intact rat liver mitochondria

Osmundsen

1978

FEBS Letters

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Section: Resultsmentioning

confidence: 99%

Effects of pent‐4‐enoate on flux through acyl‐CoA dehydrogenases of β‐oxidation in intact rat liver mitochondria

Osmundsen

1978

FEBS Letters

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“…The rates of oxygen consumption in the presence of succinate (10 mM) or glutamate (5 mM) plus malate (5 mM) were determined in the medium of Aprille and Asimakis [24], as described previously [15]. The rates of palmitoyl-CoA (40 pM) and palmitoyl-L-carnitine (40 pM) oxidation were measured in the respiratory medium of Osmundsen and Sherratt [25] as described previously [15].…”

Section: Polarographic Measurementsmentioning

confidence: 99%

Regulation of fatty acid oxidation in isolated hepatocytes and liver mitochondria from newborn rabbits

Herbin

Pégorier

Duée

et al. 1987

European Journal of Biochemistry

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The changes in long-chain fatty acid oxidation during the first 24 h after birth were studied in isolated rabbit hepatocytes and liver mitochondria. The eightfold increase in t h s oxidation which occurs in hepatocytes between birth and 24 h was not triggered by a concomitant decrease in long-chain fatty acid esterification. Indeed, in isolated hepatocytes from 24-h-old rabbits, the 75% inhibition of the oxidation by 2-tetradecylglycidic acid, resulted in a total redirection of oleate metabolized towards triacylglycerol synthesis. Polarographic measurements of mitochondrial respiration showed that oxidative phosphorylation and respiratory chain capacity were fully functional at birth. By contrast, in liver mitochondria isolated from newborn rabbits, the rate of oxygen consumption from palmitoyl-L-carnitine was 60% higher than from palmitoyl-CoA. Similarly palmitoyl-CoA oxidation was increased 1 .Sfold in isolated mitochondria from 24-h-old rabbits. These results were in agreement with the twofold increase in the activity of hepatic carnitine palmitoyltransferase I between birth and 24 h. However it is unlikely that the twofold increase in this enzyme activity totally explained the eightfold increase in long-chain fatty acid oxidation in isolated newborn rabbit hepatocytes. It was shown that the rate of the oxidation in isolated hepatocytes was inversely related to the rate of lipogenesis. Nevertheless, malonyl-CoA concentration per se is probably not the factor involved in the regulation of the oxidation between birth and 24 h, since a 90% decrease in hepatic malonyl-CoA concentration was not associated with a stimulation of long-chain fatty acid oxidation. The more likely mechanism was the 30-fold decrease in the sensitivity of carnitine palmitoyltransferase I to malonyl-CoA inhibition.

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“…was described by Osmundsen and Sherratt [35] for rat liver mitochondria. A rapid cycling of acetate and acetyl-CoA in rat hepatocytes has been described more recently [36].…”

Section: Discussionmentioning

confidence: 99%

“…A plausible explanation is that operation of this cycle has been deduced from experiments with abnormally high concentrations of medium chain fatty acids, either in perfusates or incubation media, which rarely occur in the portal vein blood under normal feeding conditions. The K m of medium-chain acyl-CoA hydrolase for hexanoyl-CoA is 0.5 mM [35]. Free 287 medium-chain acyl-AMP appears in substantial amounts as an intermediate of fatty acid activation only in the presence of large excess of its substrates [39].…”

Section: Discussionmentioning

confidence: 99%

On the mechanism of the so-called uncoupling effect of medium- and short-chain fatty acids

Schönfeld

Wojtczak

Geelen

et al. 1988

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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Octanoate applied to rat liver mitochondria respiring with glutamate plus malate or succinate (plus rotenone) under resting-state (State 4) conditions stimulates oxygen uptake and decreases the membrane potential, both effects being sensitive to oligomycin but not to carboxyatractyloside. Octanoate also decreases the rate of pyruvate carboxylation under the same conditions, this effect being correlated with the decrease of intramitochondrial content of ATP and increase of AMP. The decrease of pyruvate carboxylation and the change of mitochondrial adenine nucleotides are both reversed by 2-oxoglutarate. Fatty acids of shorter chain length have similar effects, though at higher concentrations. Addition of octanoate in the presence of fluoride (inhibitor of pyrophosphatase) produces intramitochondrial accumulation of pyropbosphate, even under conditions when oxidation of octanoate is prevented by rotenone. In isolated hepatocytes incubated with lactate plus pyruvate, octanoate also increases oxygen uptake and produces a shift in the profile of adenine nucleotides similar to that observed in isolated mitochondria. It decreases the 'efficiency' of gluconeogenesis, as expressed by the ratio between an increase of glucose production and an increase of oxygen uptake upon addition of gluconeogenic suhstrates (lactate plus pyruvate), and increases the reduction state of mitochondrial NAD. These effects taken together are not compatible with uncoupling, but point to intramitochondrial hydrolysis of octanoyl-CoA and probably also shorter chain-length acyI-CoAs. This mechanism probably functions as a 'safety valve' preventing a drastic decrease of intramitochondrial free CoA under a large supply of medium-and short-chain fatty acids.

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A Novel mechanism for inhibition of β‐oxidation by methylenecyclopropylacetyl‐CoA, a metabolite of hypoglycin

Cited by 90 publications

References 18 publications

Effects of pent‐4‐enoate on flux through acyl‐CoA dehydrogenases of β‐oxidation in intact rat liver mitochondria

Effects of pent‐4‐enoate on flux through acyl‐CoA dehydrogenases of β‐oxidation in intact rat liver mitochondria

Regulation of fatty acid oxidation in isolated hepatocytes and liver mitochondria from newborn rabbits

On the mechanism of the so-called uncoupling effect of medium- and short-chain fatty acids

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