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Nutrition clinique et métabolisme
Volume 15, n° 4
pages 266-272 (décembre 2001)
Facteurs lipolytiques et protéolytiques de la cachexie cancéreuse
Lipolytic and proteolytic factors in cancer cachexia

Michael John  Tisdale *
Pharmaceutical sciences research institute, Aston university, Birmingham B4 7ET, United Kingdom 

*Correspondance et tirés à part.
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Les patients atteints de cachexie cancéreuse présentent une perte majeure de masses maigre et grasse. La perte de masse grasse résulte tout d'abord d'une augmentation de l'hydrolyse des triglycérides sous l'action d'un facteur tumoral, le Lipid Mobilizing Factor (LMF). Le LMF induit une activation de l'adénylate cyclase adipocytaire selon un processus GTP-dépendant via sa liaison à un récepteur  -adrénergique, comme les hormones lipolytiques. La perte de masse musculaire est le résultat d'une réduction des synthèses protéique et d'une augmentation de la dégradation, cette dernière étant la conséquence d'une augmentation de l'expression du système ubiquitine-protéasome. Il a été montré que les tumeurs cachectisantes tant murines qu'humaines produisaient un facteur inducteur de la protéolyse (Proteolysis-Inducing Factor, PIF), une glycoprotéine sulfatée de 24 kDa capable d'induire une dégradation des protéines des muscles squelettiques tant in vitro que in vivo. Le PIF active ce catabolisme en induisant l'expression du système ubiquitine-protéasome, probablement par l'intermédiaire de l'acide 15-hydroxyeicosatétraèno uml;que (15-HETE). L'acide eicosapentaéno uml;que (EPA) exerce au contraire un effet protecteur, permettant un arrêt de la perte de poids chez les patients porteurs d'un carcinome non résecable du pancréas. Cela suggère qu'une meilleur connaissance des médiateurs cataboliques responsables de la cachéxie cancéreuse devrait contribuer à la mise au point de traitements efficaces.

Mots clés  : acide eicosapentaéno uml;que ; cachexie ; lipid mobilizing factor ; protéasome ; proteolysis-inducing factor.

Abstract

Patients with cancer cachexia experience a profound loss of both adipose tissue and skeletal muscle mass. Depletion of adipose tissue arises primarily from an increased hydrolysis of triglycerides mediated by a tumour factor, lipid mobilizing factor (LMF). LMF induces stimulation of adipocyte adenylate cyclase in a GTP-dependent process through binding to a  -adrenergic receptor, as for lipolytic hormones, resulting in specific depletion of carcass fat. Loss of muscle mass results from a decrease in protein synthesis and an increase in protein degradation, the latter being mediated through an increased expression of the components of the ubiquitin-proteasome pathway. Both murine and human cachexia-inducing tumours have been shown to secrete a proteolysis-inducing factor (PIF), a 24 kDa sulphated glycoprotein capable of inducing catabolism of skeletal muscle proteins both in vitro and in vivo. PIF initiates muscle protein catabolism by upregulation of the expression of the ubiquitin-proteasome pathway, possibly through the mediation of 15-hydroxyeicosatetraenoic acid (15-HETE). This process is attenuated by the polyunsaturated fatty acid, eicosapentaenoic acid (EPA), which has also been shown to completely stabilize weight loss in patients with unresectable pancreatic carcinoma. This suggests that knowledge of the catabolic mediators involved in cancer cachexia well lead to effective therapeutic intervention.

Mots clés  : cachexia ; eicosapentaenoic acid ; lipid mobilizing factor ; proteasome ; proteolysis-inducing factor.




© 2001  Éditions scientifiques et médicales Elsevier SAS. All Rights Reserved.

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