Regulation of hepatic cardiolipin metabolism by TNFα: Implication in cancer cachexia.
Cardiolipin (CL) content accumulation leads to an increase in energy wasting in liver mitochondria in a rat model of cancer cachexia in which tumor necrosis factor alpha (TNFα) is highly expressed. In this study we investigated the mechanisms involved in liver mitochondria CL accumulation in cancer cachexia and examined if TNFα was involved in this process leading to mitochondrial bioenergetics alterations. We studied gene, protein expression and activity of the main enzymes involved in CL metabolism in liver mitochondria from a rat model of cancer cachexia and in HepaRG hepatocyte-like cells exposed to 20 ng/ml of TNFα for 12 h. Phosphatidylglycerolphosphate synthase (PGPS) gene expression was increased 2.3-fold (p<0.02) and cardiolipin synthase (CLS) activity decreased 44% (p<0.03) in cachectic rat livers compared to controls. CL remodeling enzymes monolysocardiolipin acyltransferase (MLCL AT-1) activity and tafazzin (TAZ) gene expression were increased 30% (p<0.01) and 50% (p<0.02), respectively, in cachectic rat livers compared to controls. Incubation of hepatocytes with TNFα increased CL content 15% (p<0.05), mitochondrial oxygen consumption 33% (p<0.05), PGPS gene expression 44% (p<0.05) and MLCL AT-1 activity 20% (p<0.05) compared to controls. These above findings strongly suggest that in cancer cachexia, TNFα induces a higher energy wasting in liver mitochondria by increasing CL content via upregulation of PGPS expression.
Inserm UMR1069, Nutrition, Croissance et Cancer, Université François Rabelais de Tours-10, bd Tonnellé, 37032 Tours Cedex, France. Electronic address: laure.peyta@etu.univ-tours.fr.
Laure
L
Peyta
Inserm UMR S-991, Foie, Métabolismes et Cancer, CHU Pontchaillou, 2 rue Henri Le Guilloux, 35033 Rennes, France; Université de Rennes 1, 2 rue du Thabor CS46510, 35065 Rennes cedex, France. Electronic address: kathleen.jarnouen@univ-rennes1.fr.
Kathleen
K
Jarnouen
Inserm UMR1069, Nutrition, Croissance et Cancer, Université François Rabelais de Tours-10, bd Tonnellé, 37032 Tours Cedex, France. Electronic address: michelle.pinault@univ-tours.fr.
Michelle
M
Pinault
Inserm UMR S-991, Foie, Métabolismes et Cancer, CHU Pontchaillou, 2 rue Henri Le Guilloux, 35033 Rennes, France; Université de Rennes 1, 2 rue du Thabor CS46510, 35065 Rennes cedex, France. Electronic address: cedric.coulouarn@univ-rennes1.fr.
Cedric
C
Coulouarn
Inserm UMR1069, Nutrition, Croissance et Cancer, Université François Rabelais de Tours-10, bd Tonnellé, 37032 Tours Cedex, France. Electronic address: cyrille.guimaraes@gmail.com.
Cyrille
C
Guimaraes
Inserm UMR1069, Nutrition, Croissance et Cancer, Université François Rabelais de Tours-10, bd Tonnellé, 37032 Tours Cedex, France; CHRU de Tours, Département de Médecine Interne, 2, bd Tonnellé, 37044 Tours cedex 9, France. Electronic address: caroline.goupille@univ-tours.fr.
Caroline
C
Goupille
Plateforme de Lipidomique. INSERM UMR866/LabEx LipSTIC, 15 Bd Mal de Lattre de Tassigny, 21000 Dijon, France. Electronic address: jppais@u-bourgogne.fr.
Jean-Paul Pais
JP
de Barros
Inserm UMR1069, Nutrition, Croissance et Cancer, Université François Rabelais de Tours-10, bd Tonnellé, 37032 Tours Cedex, France. Electronic address: stephan.chevalier@univ-tours.fr.
Stephan
S
Chevalier
Inserm UMR1069, Nutrition, Croissance et Cancer, Université François Rabelais de Tours-10, bd Tonnellé, 37032 Tours Cedex, France. Electronic address: jean-francois.dumas@univ-tours.fr.
Jean-François
JF
Dumas
Inserm UMR1069, Nutrition, Croissance et Cancer, Université François Rabelais de Tours-10, bd Tonnellé, 37032 Tours Cedex, France; CHRU de Tours, Département de Médecine Interne, 2, bd Tonnellé, 37044 Tours cedex 9, France. Electronic address: maillot@med.univ-tours.fr.
François
F
Maillot
Department of Pharmacology and Therapeutics, Biochemistry and Medical Genetics, Faculty of Health Sciences, Center for Research and Treatment of Atherosclerosis, DREAM Children's Hospital Research Institute of Manitoba, University of Manitoba, 513-715 McDermot Avenue, Winnipeg R3E 3P4, Manitoba, Canada. Electronic address: ghatch@chrim.ca.
Grant M
GM
Hatch
Inserm UMR S-991, Foie, Métabolismes et Cancer, CHU Pontchaillou, 2 rue Henri Le Guilloux, 35033 Rennes, France; Université de Rennes 1, 2 rue du Thabor CS46510, 35065 Rennes cedex, France. Electronic address: pascal.loyer@univ-rennes1.fr.
Pascal
P
Loyer
Inserm UMR1069, Nutrition, Croissance et Cancer, Université François Rabelais de Tours-10, bd Tonnellé, 37032 Tours Cedex, France. Electronic address: stephane.servais@univ-tours.fr.
Stephane
S
Servais
D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002100:Cachexia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002308:Cardiolipins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
D002308:Cardiolipins; D008565:Membrane Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000217:Acyltransferases; C544439:Tafazzin protein, rat; C401969:monolysocardiolipin acyltransferase; D017855:Transferases (Other Substituted Phosphate Groups); C100091:cardiolipin synthetase; C020676:CDP-diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase
Cardiolipin biosynthesis; Cardiolipin remodeling; Cytokines; Energy wasting; Inflammation; Liver; Mitochondria