title: Long-chain acyl coenzyme A synthetase 1 overexpression in primary cultured Schwann cells prevents long chain fatty acid-induced oxidative stress and mitochondrial dysfunction.
abstract: OBJECTIVE
  High circulating long chain fatty acids (LCFAs) are implicated in diabetic neuropathy (DN) development. Expression of the long-chain acyl-CoA synthetase 1 (Acsl1) gene, a gene required for LCFA metabolic activation, is altered in human and mouse diabetic peripheral nerve. We assessed the significance of Acsl1 upregulation in primary cultured Schwann cells.
  
  
  RESULTS
  Acsl1 overexpression prevented oxidative stress (nitrotyrosine; hydroxyoctadecadienoic acids [HODEs]) and attenuated cellular injury (TUNEL) in Schwann cells following 12 h exposure to LCFAs (palmitate, linoleate, and oleate, 100 μM). Acsl1 overexpression potentiated the observed increase in medium to long-chain acyl-carnitines following 12 h LCFA exposure. Data are consistent with increased mitochondrial LCFA uptake, largely directed to incomplete beta-oxidation. LCFAs uncoupled mitochondrial oxygen consumption from ATP production. Acsl1 overexpression corrected mitochondrial dysfunction, increasing coupling efficiency and decreasing proton leak.
  
  
  METHODS
  Schwann cell mitochondrial function is critical for peripheral nerve function, but research on Schwann cell mitochondrial dysfunction in response to hyperlipidemia is minimal. We demonstrate that high levels of a physiologically relevant mixture of LCFAs induce Schwann cell injury, but that improved mitochondrial uptake and metabolism attenuate this lipotoxicity.
  
  
  CONCLUSIONS
  Acsl1 overexpression improves Schwann cell function and survival following high LCFA exposure in vitro; however, the observed endogenous Acsl1 upregulation in peripheral nerve in response to diabetes is not sufficient to prevent the development of DN in murine models of DN. Therefore, targeted improvement in Schwann cell metabolic disposal of LCFAs may improve DN phenotypes.
authors.affiliation: 1 Department of Neurology, University of Michigan , Ann Arbor, Michigan.
authors.forename: Lucy M
authors.initials: LM
authors.lastname: Hinder
authors.forename: Claudia
authors.initials: C
authors.lastname: Figueroa-Romero
authors.forename: Crystal
authors.initials: C
authors.lastname: Pacut
authors.forename: Yu
authors.initials: Y
authors.lastname: Hong
authors.forename: Anuradha
authors.initials: A
authors.lastname: Vivekanandan-Giri
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Pennathur
authors.forename: Eva L
authors.initials: EL
authors.lastname: Feldman
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003066:Coenzyme A Ligases / Q000235:genetics*; D003929:Diabetic Neuropathies / Q000378:metabolism; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism* / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010101:Oxygen Consumption; D061251:Primary Cell Culture; D051381:Rats; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; C544400:ACSL1 protein, mouse; D003066:Coenzyme A Ligases