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Originally published In Press as doi:10.1194/jlr.M400464-JLR200 on March 1, 2005

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Journal of Lipid Research, Vol. 46, 1133-1149, June 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Mitochondrial dysfunction induces triglyceride accumulation in 3T3-L1 cells: role of fatty acid ß-oxidation and glucose

Sébastien Vankoningsloo, Marie Piens, Christophe Lecocq, Audrey Gilson, Aurélia De Pauw, Patricia Renard, Catherine Demazy, Andrée Houbion, Martine Raes and Thierry Arnould1

Laboratory of Biochemistry and Cellular Biology, University of Namur, 5000 Namur, Belgium

Published, JLR Papers in Press, March 1, 2005. DOI 10.1194/jlr.M400464-JLR200

1 To whom correspondence should be addressed. e-mail: thierry.arnould{at}fundp.ac.be

Mitochondrial cytopathy has been associated with modifications of lipid metabolism in various situations, such as the acquisition of an abnormal adipocyte phenotype observed in multiple symmetrical lipomatosis or triglyceride (TG) accumulation in muscles associated with the myoclonic epilepsy with ragged red fibers syndrome. However, the molecular signaling leading to fat metabolism dysregulation in cells with impaired mitochondrial activity is still poorly understood. Here, we found that preadipocytes incubated with inhibitors of mitochondrial respiration such as antimycin A (AA) accumulate TG vesicles but do not acquire specific markers of adipocytes. Although the uptake of TG precursors is not stimulated in 3T3-L1 cells with impaired mitochondrial activity, we found a strong stimulation of glucose uptake in AA-treated cells mediated by calcium and phosphatidylinositol 3-kinase/Akt1/glycogen synthase kinase 3ß, a pathway known to trigger the translocation of glucose transporter 4 to the plasma membrane in response to insulin. TG accumulation in AA-treated cells is mediated by a reduced peroxisome proliferator-activated receptor {gamma} activity that downregulates muscle carnitine palmitoyl transferase-1 expression and fatty acid ß-oxidation, and by a direct conversion of glucose into TGs accompanied by the activation of carbohydrate-responsive element binding protein, a lipogenic transcription factor.

Taken together, these results could explain how mitochondrial impairment leads to the multivesicular phenotype found in some mitochondria-originating diseases associated with a dysfunction in fat metabolism.

Abbreviations: AA, antimycin A; ACC, acetyl-coenzyme A carboxylase; AICAR, 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside; AMPK, AMP-dependent kinase; BAPTA-AM, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; C/EBPß, CCAAT/enhancer-binding protein ß; ChREBP, carbohydrate-responsive element binding protein; 2-DG, 2-deoxy-D-[3H]glucose; EGCG, (–)-epigallocatechin gallate; FABP4, fatty acid binding protein 4; FCCP, carbonyl cyanide (p-trifluoromethoxy)phenylhydrazone; FCS, fetal calf serum; GLUT, glucose transporter; GSK3ß, glycogen synthase kinase 3ß; HB, hypotonic buffer; IRS-1, insulin receptor substrate-1; L-PK, liver pyruvate kinase; M-CPT-1, muscle carnitine palmitoyl transferase-1; MERRF, myoclonic epilepsy with ragged red fibers; MSL, multiple symmetrical lipomatosis; NAC, N-acetyl-L-cysteine; PI 3-kinase, phosphatidylinositol 3-kinase; PPAR{gamma}, peroxisome proliferator-activated receptor {gamma}; ROS, reactive oxygen species; RXR{alpha}, retinoid X receptor {alpha}; TBP, TATA box binding protein; TG, triglyceride; UCP-2, uncoupling protein-2

Supplementary key words muscle carnitine palmitoyl transferase-1 • phosphatidylinositol 3-kinase/Akt1/glycogen synthase kinase 3ß • AMP-dependent kinase • carbohydrate-responsive element binding protein • peroxisome proliferator-activated receptor {gamma}


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