Liver mitochondrial β-oxidation of LCFAs (long-chain fatty acids) is tightly regulated through inhibition of CPT1A (carnitine palmitoyltransferase 1A) by malonyl-CoA, an intermediate of lipogenesis stimulated by glucose and insulin. Moreover, CPT1A sensitivity to malonyl-CoA inhibition varies markedly depending on the physiopathological state of the animal. In the present study, we asked whether an increase in CPT1A activity solely or in association with a decreased malonyl-CoA sensitivity could, even in the presence of high glucose and insulin concentrations, maintain a sustained LCFA β-oxidation and/or protect from triacylglycerol (triglyceride) accumulation in hepatocytes. We have shown that adenovirus-mediated expression of rat CPT1wt (wild-type CPT1A) and malonyl-CoA-insensitive CPT1mt (CPT1AM593S mutant) in cultured fed rat hepatocytes counteracted the inhibition of oleate β-oxidation induced by 20 mM glucose/10 nM insulin. Interestingly, the glucose/insulin-induced cellular triacylglycerol accumulation was prevented, both in the presence and absence of exogenous oleate. This resulted from the generation of a metabolic switch allowing β-oxidation of de novo synthesized LCFAs, which occurred without alteration in glucose oxidation and glycogen synthesis. Moreover, CPT1mt expression was more effective than CPT1wt overexpression to counteract glucose/insulin effects, demonstrating that control of CPT1A activity by malonyl-CoA is an essential driving force for hepatic LCFA metabolic fate. In conclusion, the present study highlights that CPT1A is a prime target to increase hepatic LCFA β-oxidation and that acting directly on the degree of its malonyl-CoA sensitivity may be a relevant strategy to prevent and/or correct hepatic steatosis.
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Research Article|
May 27 2009
Modulation of the hepatic malonyl-CoA–carnitine palmitoyltransferase 1A partnership creates a metabolic switch allowing oxidation of de novo fatty acids1
Marie Akkaoui;
Marie Akkaoui
*Institut Cochin, Département d'Endocrinologie, Métabolisme et Cancer, Université Paris Descartes, CNRS Unité Mixte de Recherche 8104
†INSERM U567, 24 rue du Faubourg Saint-Jacques, 75014 Paris, France
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Isabelle Cohen;
Isabelle Cohen
*Institut Cochin, Département d'Endocrinologie, Métabolisme et Cancer, Université Paris Descartes, CNRS Unité Mixte de Recherche 8104
†INSERM U567, 24 rue du Faubourg Saint-Jacques, 75014 Paris, France
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Catherine Esnous;
Catherine Esnous
*Institut Cochin, Département d'Endocrinologie, Métabolisme et Cancer, Université Paris Descartes, CNRS Unité Mixte de Recherche 8104
†INSERM U567, 24 rue du Faubourg Saint-Jacques, 75014 Paris, France
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Véronique Lenoir;
Véronique Lenoir
*Institut Cochin, Département d'Endocrinologie, Métabolisme et Cancer, Université Paris Descartes, CNRS Unité Mixte de Recherche 8104
†INSERM U567, 24 rue du Faubourg Saint-Jacques, 75014 Paris, France
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Martin Sournac;
Martin Sournac
*Institut Cochin, Département d'Endocrinologie, Métabolisme et Cancer, Université Paris Descartes, CNRS Unité Mixte de Recherche 8104
†INSERM U567, 24 rue du Faubourg Saint-Jacques, 75014 Paris, France
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Jean Girard;
Jean Girard
*Institut Cochin, Département d'Endocrinologie, Métabolisme et Cancer, Université Paris Descartes, CNRS Unité Mixte de Recherche 8104
†INSERM U567, 24 rue du Faubourg Saint-Jacques, 75014 Paris, France
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Carina Prip-Buus
Carina Prip-Buus
2
*Institut Cochin, Département d'Endocrinologie, Métabolisme et Cancer, Université Paris Descartes, CNRS Unité Mixte de Recherche 8104
†INSERM U567, 24 rue du Faubourg Saint-Jacques, 75014 Paris, France
2To whom correspondence should be addressed (email carina.prip@inserm.fr).
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Publisher: Portland Press Ltd
Received:
September 24 2008
Revision Received:
March 02 2009
Accepted:
March 20 2009
Accepted Manuscript online:
March 20 2009
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem J (2009) 420 (3): 429–438.
Article history
Received:
September 24 2008
Revision Received:
March 02 2009
Accepted:
March 20 2009
Accepted Manuscript online:
March 20 2009
Citation
Marie Akkaoui, Isabelle Cohen, Catherine Esnous, Véronique Lenoir, Martin Sournac, Jean Girard, Carina Prip-Buus; Modulation of the hepatic malonyl-CoA–carnitine palmitoyltransferase 1A partnership creates a metabolic switch allowing oxidation of de novo fatty acids. Biochem J 15 June 2009; 420 (3): 429–438. doi: https://doi.org/10.1042/BJ20081932
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