Lack of sterol regulatory element binding factor-1c imposes glial fatty acid utilization leading to peripheral neuropathy

Gaia Cermenati, Matteo Audano, Silvia Giatti, Valentina Carozzi, Carla Porretta-Serapiglia, Emanuela Pettinato, Cinzia Ferri, Maurizio D'Antonio, Emma De Fabiani, Maurizio Crestani, Samuele Scurati, Enrique Saez, Iñigo Azcoitia, Guido Cavaletti, Luis Miguel Garcia-Segura, Roberto C. Melcangi, Donatella Caruso, Nico Mitro

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)571-583
Number of pages13
JournalCell Metabolism
Volume21
Issue number4
DOIs
Publication statusPublished - Apr 7 2015

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

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