Combination of lipid metabolism alterations and their sensitivity to inflammatory cytokines in human lipin-1-deficient myoblasts

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1832

Article

Michot, Caroline^1,2  Mamoune, Asmaa^1,2  Vamecq, Joseph^3,4  Mai Thao Viou⁵  Hsieh, Lu-Sheng^6,7  Testet, Eric⁸  Laine, Jeanne^9,10  Hubert, Laurence^1,2  Dessein, Anne-Frederique^3,4  Fontaine, Monique^3,4  Ottolenghi, Chris^1,2  Fouillen, Laetitia⁸  Nadra, Karim¹¹  Blanc, Etienne^12,13  Bastin, Jean^12,13  Candon, Sophie¹⁴  Pende, Mario¹¹  Munnich, Arnold^1,2  Smahi, Asma^1,2  Djouadi, Fatima^12,13  Carman, George M.^6,7  Romero, Norma⁵  de Keyzer, Yves^1,2  de Lonlay, Pascale^1,2 

[1] Paris Descartes Univ, INSERM, U781, F-75015 Paris, France

[2] Hop Necker Enfants Malad, AP HP, Ctr Reference Malad Hereditaires Metab, F-75015 Paris, France

[3] CHRU Lille, INSERM, HMNO, CBP, Lille, France

[4] CHRU Lille, Lab Biochim & Biol Mol, HMNO, CBP, Lille, France

[5] Univ Paris 06, CNRS,UM 76, GHU Pitie Salpetriere,Inst Myol,Inserm,UMR 7215, AP HP,Ctr Reference Malad Neuromusculaires,U974, Paris, France

[6] Rutgers State Univ, Dept Food Sci, New Brunswick, NJ 08903 USA

[7] Rutgers State Univ, Rutgers Ctr Lipid Res, New Brunswick, NJ 08903 USA

[8] Univ Bordeaux Segalen, CNRS, UMR 5200, Lab Biogenese Membranaire, Bordeaux, France

[9] INSERM, U974, Paris, France

[10] Univ Paris 06, Dept Physiol, Paris, France

[11] Paris Descartes Univ, INSERM, U845, F-75015 Paris, France

[12] INSERM, U747, Paris, France

[13] Paris Descartes Univ, APHP, F-75015 Paris, France

[14] Paris Descartes Univ, INSERM, U1013, F-75015 Paris, France

关键词: Rhabdomyolysis;    Lipin-1;    PAP1;    ACACB;    Lipid droplet;    Inflammation;   

DOI  :  10.1016/j.bbadis.2013.07.021

来源: Elsevier

【 摘 要 】

Lipin-1 deficiency is associated with massive rhabdomyolysis episodes in humans, precipitated by febrile illnesses. Despite well-known roles of lipin-1 in lipid biosynthesis and transcriptional regulation, the pathogenic mechanisms leading to rhabdomyolysis remain unknown. Here we show that primary myoblasts from lipin-1-deficient patients exhibit a dramatic decrease in LPIN1 expression and phosphatidic acid phosphatase 1 activity, and a significant accumulation of lipid droplets (LD). The expression levels of LPIN1-target genes [peroxisome proliferator-activated receptors delta and alpha (PPAR delta, PPAR alpha), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha), acyl-coenzyme A dehydrogenase, very long (ACADVL), camitine palmitoyltransferase IB and 2 (CPT1B and CPT2)] were not affected while lipin-2 protein level, a closely related member of the family, was increased. Microarray analysis of patients' myotubes identified 19 down-regulated and 51 up-regulated genes, indicating pleiotropic effects of lipin-1 deficiency. Special attention was paid to the up-regulated ACACB (acetyl-CoA carboxylase beta), a key enzyme in the fatty acid synthesis/oxidation balance. We demonstrated that overexpression of ACACB was associated with free fatty acid accumulation in patients' myoblasts whereas malonyl-camitine (as a measure of malonyl-CoA) and CPT1 activity were in the normal range in basal conditions accordingly to the normal daily activity reported by the patients. Remarkably ACACB invalidation in patients' myoblasts decreased LD number and size while LPIN1 invalidation in controls induced LD accumulation. Further, pro-inflammatory treatments tumor necrosis factor alpha + Interleukin-1beta(TNF1 alpha + IL-1 beta) designed to mimic febrile illness, resulted in increased malonyl-camitine levels, reduced CPT1 activity and enhanced LD accumulation, a phenomenon reversed by dexamethasone and TNF alpha. or IL-1 beta inhibitors. Our data suggest that the pathogenic mechanism of rhabdomyolysis in lipin-1-deficient patients combines the predisposing constitutive impairment of lipid metabolism and its exacerbation by pro-inflammatory cytokines. (C) 2013 Published by Elsevier B.V.

【 授权许可】

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