title: Lack of sterol regulatory element binding factor-1c imposes glial Fatty Acid utilization leading to peripheral neuropathy.
abstract: Myelin is a membrane characterized by high lipid content to facilitate impulse propagation. Changes in myelin fatty acid (FA) composition have been associated with peripheral neuropathy, but the specific role of peripheral nerve FA synthesis in myelin formation and function is poorly understood. We have found that mice lacking sterol regulatory element-binding factor-1c (Srebf1c) have blunted peripheral nerve FA synthesis that results in development of peripheral neuropathy. Srebf1c-null mice develop Remak bundle alterations and hypermyelination of small-caliber fibers that impair nerve function. Peripheral nerves lacking Srebf1c show decreased FA synthesis and glycolytic flux, but increased FA catabolism and mitochondrial function. These metabolic alterations are the result of local accumulation of two endogenous peroxisome proliferator-activated receptor-α (Pparα) ligands, 1-palmitoyl-2-oleyl-sn-glycerol-3-phosphatidylcholine and 1-stearoyl-2-oleyl-sn-glycerol-3-phosphatidylcholine. Treatment with a Pparα antagonist rescues the neuropathy of Srebf1c-null mice. These findings reveal the importance of peripheral nerve FA synthesis to sustain myelin structure and function.
authors: DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, 20133, Italy.
authors: Gaia
authors: G
authors: Cermenati
authors: DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, 20133, Italy.
authors: Matteo
authors: M
authors: Audano
authors: DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, 20133, Italy.
authors: Silvia
authors: S
authors: Giatti
authors: Experimental Neurology Unit, Department of Surgery and Translational Medicine, Università degli Studi Milano-Bicocca, Monza, 20052, Italy.
authors: Valentina
authors: V
authors: Carozzi
authors: IRCCS Foundation, Carlo Besta Neurological Institute, Milano, 20133, Italy.
authors: Carla
authors: C
authors: Porretta-Serapiglia
authors: Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, DIBIT, Milano, 20132, Italy.
authors: Emanuela
authors: E
authors: Pettinato
authors: Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, DIBIT, Milano, 20132, Italy.
authors: Cinzia
authors: C
authors: Ferri
authors: Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, DIBIT, Milano, 20132, Italy.
authors: Maurizio
authors: M
authors: D'Antonio
authors: DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, 20133, Italy.
authors: Emma
authors: E
authors: De Fabiani
authors: DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, 20133, Italy.
authors: Maurizio
authors: M
authors: Crestani
authors: DASP s.r.l., Gerenzano, 21040, Italy.
authors: Samuele
authors: S
authors: Scurati
authors: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors: Enrique
authors: E
authors: Saez
authors: Departamento de Biología Celular, Facultad de Biología, Universidad Complutense de Madrid, Madrid, E-28040, Spain.
authors: Iñigo
authors: I
authors: Azcoitia
authors: Experimental Neurology Unit, Department of Surgery and Translational Medicine, Università degli Studi Milano-Bicocca, Monza, 20052, Italy.
authors: Guido
authors: G
authors: Cavaletti
authors: Instituto Cajal, C.S.I.C., Madrid, E-28002, Spain.
authors: Luis-Miguel
authors: LM
authors: Garcia-Segura
authors: DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, 20133, Italy.
authors: Roberto C
authors: RC
authors: Melcangi
authors: DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, 20133, Italy. Electronic address: donatella.caruso@unimi.it.
authors: Donatella
authors: D
authors: Caruso
authors: DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, 20133, Italy. Electronic address: nico.mitro@unimi.it.
authors: Nico
authors: N
authors: Mitro
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D005227:Fatty Acids / Q000378:metabolism*; D055432:Metabolomics; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D046529:Microscopy, Electron, Transmission; D009186:Myelin Sheath / Q000378:metabolism* / Q000648:ultrastructure; D009457:Neuroglia / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology; D047493:PPAR alpha / Q000037:antagonists & inhibitors; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000172:deficiency*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D005227:Fatty Acids; C449302:GW 6471; D010080:Oxazoles; D047493:PPAR alpha; D051780:Sterol Regulatory Element Binding Protein 1; D014443:Tyrosine