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Journal of Lipid Research, Vol. 50, 135-147, January 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Silencing of Abcd1 and Abcd2 genes sensitizes astrocytes for inflammation: implication for X-adrenoleukodystrophy^*

Jaspreet Singh, Mushfiquddin Khan and Inderjit Singh¹

Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC

^* This study was supported in part by The National Institutes of Health, Grants NS-22576, NS-34741, NS-37766, NS-40810, C06 RR-018823, and C06 RR-015455.

Published, JLR Papers in Press, August 31, 2008.

¹ To whom correspondence should be addressed. e-mail: singhi{at}musc.edu

X-linked adrenoleukodystrophy is a metabolic disorder arising from a mutation/deletion in the ABCD1 gene, leading to a defect in the peroxisomal adrenoleukodystrophy protein (ALDP), which inhibits the oxidation of very long chain fatty acids (VLCFAs). Thus, these VLCFAs accumulate. In a cerebral form of ALD (cALD), VLCFA accumulation induces neuroinflammation that leads to loss of oligodendrocytes and myelin, which ultimately shortens the lifespan. To establish a relationship between the metabolic disease and inflammatory disease induction, we document that small interfering RNA (siRNA)-mediated silencing of Abcd1 (ALDP) and Abcd2 [adrenoleukodystrophy-related protein (ALDRP)] genes in mice primary astrocyte cultures resulted in accumulation of VLCFA and induction of an inflammatory response characteristic of human cALD. Correction of the metabolic defect using monoenoic FAs in Abcd1/Abcd2-silenced cultured astrocytes decreased inducible nitric oxide synthase and inflammatory cytokine expression, suggesting a link between VLCFA accumulation and inflammation. The inflammatory response was found to be mediated by transcription factors NF-B, AP-1, and C/EBP in Abcd1/Abcd2-silenced mouse primary astrocytes. Although mechanisms of VLCFA-mediated induction of the inflammatory response have been investigated here in vitro, the in vivo mediators remain elusive. Our data represent the first study to suggest a direct link between the accumulation of VLCFA and the induction of inflammatory mediators.

Supplementary key words peroxisomes • very long chain fatty acids • glia • nitric oxide • cytokines • adrenoleukodystrophy protein • adrenoleukodystrophy-related protein

Abbreviations: ALDP, adrenoleukodystrophy protein; ALDRP, adrenoleukodystrophy-related protein; AMN, adrenomyeloneuropathy; cALD, cerebral adrenoleukodystrophy; CNS, central nervous system; COX-2, cycloxygenase-2; EMSA, electrophoretic mobility shift assay; FAME, fatty acid methyl ester; IL-1β, interleukin-1β; iNOS, inducible nitric oxide synthase; LO, Lorenzo's Oil; 5-LOX, 5-lipoxygenase; NO, nitric oxide; PPAR, peroxisome proliferator-activated receptor; ROS, reactive oxygen species; Scr, scrambled; TNF-, tumor necrosis factor-; VLCFA, very long chain fatty acid; X-ALD, X-linked adrenoleukodystrophy

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