Long-Chain Acyl Coenzyme A Synthetase 1 Overexpression in Primary Cultured
Schwann Cells Prevents Long Chain Fatty Acid-Induced Oxidative Stress and
Mitochondrial Dysfunction.
Authors Hinder LM, Figueroa-Romero C, Pacut C, Hong Y, Vivekanandan-Giri A, Pennathur S,
Feldman EL
Submitted By Eva Feldman on 4/15/2014
Status Published
Journal Antioxidants & redox signaling
Year 2013
Date Published 10/5/2013
Volume : Pages 21 : 588 - 600
PubMed Reference 23991914
Abstract Abstract Aims: 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. Innovation: 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. Conclusion: 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. Antioxid.
Redox Signal. 00, 000-000.

Investigators with authorship
Eva FeldmanUniversity of Michigan