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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Vamecq, Joseph Hubert, Laurence Pende, Mario De Lonlay, Pascale De Keyzer, Yves Fontaine, Monique Ottolenghi, Chris Dessein, Anne-frédérique Djouadi, Fatima Nadra, Karim Blanc, Etienne Carman, George M. Fouillen, Laetitia Hsieh, Lu-sheng Bastin, Jean Testet, Eric Lainé, Jeanne Munnich, Arnold Smahi, Asma Michot, Caroline Viou, Mai Thao Candon, Sophie Romero, Norma Mamoune, Asmaa |
| Description | Author Affiliation: Michot C ( Inserm U781, Imagine Institut des Maladies Génétiques, Université Paris Descartes et Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Necker, AP-HP, Paris, France.) |
| Abstract | 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 (PPARδ, PPAR ), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 ), acyl-coenzyme A dehydrogenase, very long (ACADVL), carnitine 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-carnitine (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 +IL-1ß) designed to mimic febrile illness, resulted in increased malonyl-carnitine levels, reduced CPT1 activity and enhanced LD accumulation, a phenomenon reversed by dexamethasone and TNF or IL-1ß 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. |
| ISSN | 00063002 |
| Journal | Biochimica et Biophysica Acta (BBA) - Reviews on Cancer |
| Issue Number | 12 |
| Volume Number | 1832 |
| Language | English |
| Publisher | Elsevier |
| Publisher Date | 2013-12-01 |
| Publisher Place | Netherlands |
| Access Restriction | Open |
| Subject Keyword | Cytokines Pharmacology Inflammation Mediators Lipid Metabolism Disorders Etiology Lipids Muscle Fibers, Skeletal Pathology Myoblasts Phosphatidate Phosphatase Genetics Biological Markers Metabolism Blotting, Western Case-Control Studies Cell Cycle Cell Proliferation Child, Preschool Endoplasmic Reticulum Stress Gene Expression Profiling Drug Effects Muscle, Skeletal Mutation Oligonucleotide Array Sequence Analysis RNA, Messenger Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Rhabdomyolysis Comparative Study Research Support, Non-U.S. Gov't Biochemistry |
| Content Type | Text |
| Resource Type | Article |
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