Interacting effects of <scp>l</scp>-carnitine and malonyl-CoA on rat liver carnitine palmitoyltransferase

Bird, Michael I.; Saggerson, E D

doi:10.1042/bj2300161

Cited by 31 publications

(14 citation statements)

References 21 publications

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“…An hypersensitivity of CPT I to malonylCoA has been also described in mammalian non-hepatic tissues, including man [27,42 -441. A decreased sensitivity of CPT 1 to malonyl-CoA could theoretically result from several factors such as a decreased affinity for malonyl-CoA and/ or modifications in the K, for its substrates, both of these compounds interacting tightly in the control of CPT I [45].…”

Section: Resultsmentioning

confidence: 99%

“…By contrast, the Substrate kinetics are unchanged between birth and 24-h-old newborns (Table 6). If the apparent K , for palmitoyl-CoA is in the range to that usually found in adult rat liver and nonhepatic tissues (30 -60 pM [27,44]), the K, for carnitine is 4 -6-fold higher than in adult rat liver [27,44,45]. Such a high K, for carnitine is probably related to the hypersensitivity of newborn rabbit liver CPT I to malonyl-CoA, as has been suggested in adult rat, because of the relationship existing between IC50 and K, for carnitine [27].…”

Section: Effects Of Inhibition Of Lipogenesis On Fatty Acid Oxidationmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Effects Of Inhibition Of Lipogenesis On Fatty Acid Oxidationmentioning

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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“…It also explains the competitive relationship between MCoA and carnitine during catalysis, e.g. MCoA increases K m for carnitine (12,55). It is therefore evident that the binding of MCoA and carnitine/ PCoA is structurally distinct at the carnitine-binding pocket.…”

Section: Root Mean Square Deviations From Experimental Dihedral Restrmentioning

confidence: 89%

An Environment-dependent Structural Switch Underlies the Regulation of Carnitine Palmitoyltransferase 1A

Rao

Warren

Estolt-Povedano

et al. 2011

Journal of Biological Chemistry

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Background:The enzyme carnitine palmitoyltransferase 1 regulates the rate of fatty acid oxidation. Results: The regulatory domain of the enzyme constitutes an amphiphilic structural switch. Conclusion:The switch can integrate enzyme inhibitor concentration and membrane characteristics into one regulatory signal. Significance: This represents a highly sophisticated regulatory mechanism for enzymes residing at the membrane-water interface.

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“…4C) [32]. Several authors reported the competition between malonyl-CoA and carnitine [45,46]. The carboxylate group of malonyl-CoA and C75-CoA may partially mimic the interaction between the enzyme and the carboxylate group of carnitine, thus preventing the positioning of this substrate and inhibiting the catalytic activity of the enzyme.…”

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confidence: 99%

C75 is converted to C75-CoA in the hypothalamus, where it inhibits carnitine palmitoyltransferase 1 and decreases food intake and body weight

Mera

Bentebibel

López-Viñas

et al. 2009

Biochemical Pharmacology

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runathan, et al.. C75 is converted to C75-CoA in the hypothalamus, where it inhibits carnitine palmitoyltransferase 1 and decreases food intake and body weight. Biochemical Pharmacology, Elsevier, 2009, 77 (6) 20-11-2008 Please cite this article as: Mera P, Bentebibel A, López-Viñas E, Cordente AG, Gurunathan C, Sebastián D, Vázquez I, Herrero L, Ariza X, Gómez-Puertas P, Asins G, Serra D, García J, Hegardt FG, C75 is converted to C75-CoA in the hypothalamus, where it inhibits carnitine palmitoyltransferase 1 and decreases food intake and body weight, Biochemical Pharmacology (2008Pharmacology ( ), doi:10.1016Pharmacology ( /j.bcp.2008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 ABSTRACT Central nervous system administration of C75 produces hypophagia and weight loss in rodents identifying C75 as a potential drug against obesity and type 2 diabetes.However, the mechanism underlying this effect is unknown. Here we show that C75-CoA is generated chemically, in vitro and in vivo from C75 and that it is a potent inhibitor of carnitine palmitoyltranferase 1 (CPT1), the rate-limiting step of fatty acid oxidation. Three-D docking and kinetic analysis support the inhibitory effect of C75-CoA on CPT1. Central nervous system administration of C75 in rats led to C75-CoA production, inhibition of CPT1 and lower body weight and food intake. Our results suggest that inhibition of CPT1, and thus increased availability of fatty acids in the hypothalamus, contribute to the pharmacological mechanism of C75 to decrease food intake.

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Interacting effects of l-carnitine and malonyl-CoA on rat liver carnitine palmitoyltransferase

Cited by 31 publications

References 21 publications

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

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

An Environment-dependent Structural Switch Underlies the Regulation of Carnitine Palmitoyltransferase 1A

C75 is converted to C75-CoA in the hypothalamus, where it inhibits carnitine palmitoyltransferase 1 and decreases food intake and body weight

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