Lack of Sterol Regulatory Element Binding Factor-1c Imposes Glial Fatty Acid Utilization Leading to Peripheral Neuropathy

• Published in: Cell metabolism 2015-04, Vol.21 (4), p.571-583
• Main Authors: Cermenati, Gaia, Audano, Matteo, Giatti, Silvia, Carozzi, Valentina, Porretta-Serapiglia, Carla, Pettinato, Emanuela, Ferri, Cinzia, D’Antonio, Maurizio, De Fabiani, Emma, Crestani, Maurizio, Scurati, Samuele, Saez, Enrique, Azcoitia, Iñigo, Cavaletti, Guido, Garcia-Segura, Luis-Miguel, Melcangi, Roberto C., Caruso, Donatella, Mitro, Nico
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Blotting, Western; Chromatography, High Pressure Liquid; Fatty Acids - metabolism; Metabolomics; Mice; Mice, Knockout; Microarray Analysis; Microscopy, Electron, Transmission; Myelin Sheath - metabolism; Myelin Sheath - ultrastructure; Neuroglia - metabolism; Oxazoles - pharmacology; Peripheral Nervous System Diseases - drug therapy; Peripheral Nervous System Diseases - etiology; Peripheral Nervous System Diseases - metabolism; PPAR alpha - antagonists & inhibitors; Real-Time Polymerase Chain Reaction; Sterol Regulatory Element Binding Protein 1 - deficiency; Tyrosine - analogs & derivatives; Tyrosine - pharmacology
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2015.02.016

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. [Display omitted] •Srebf1c KO mice have blunted nerve FA synthesis and develop peripheral neuropathy•Reduced nerve FA synthesis results in accretion of Pparα ligands in Schwann cells•Increased Pparα signaling in peripheral nerves alters myelin structure/function•Treatment with a Pparα antagonist rescues the neuropathy of Srebf1c KO mice Cermenati et al. look at the specific role of fatty acid synthesis in peripheral neuropathy and show that loss of Srebf1c not only results in decreased fatty acid synthesis but also increased fatty acid oxidation due to increased Pparα activity. Pparα antagonist treatment rescues the neuropathy of Srebf1c-null mice.