Oxidative Imbalance in Nonstimulated X-Adrenoleukodystrophy-Derived Lymphoblasts

Abstract

X-Adrenoleukodystrophy (X-ALD) is a peroxisomal disorder characterized by accumulation of very long chain (VLC) fatty acids, which induces alterations in cellular redox and induction of inflammatory disease, both of which are reported to play a role in pathogenesis of the severe form of the disease (childhood ALD). Here we report on the status of oxidative stress (NADPH oxidase activity) and inflammatory mediators in a X-ALD lymphoblast cell line under non-stimulated conditions. X-ALD lymphoblasts contain near 7 fold higher levels of the C26:0 fatty acid, as compared to controls; levels that were down regulated by treatment with Sodium Phenylacetate (NaPA), lovastatin or combination of both drugs. In addition, free radical synthesis was elevated in X-ALD lymphoblasts, and protein levels of the NADPH oxidase gp91 PHOX membrane subunit were significantly upregulated, but no changes were observed in the p47 PHOX and p67 PHOX cytoplasmic subunits. Unexpectedly, there was no increase in gp91 PHOX mRNA levels in X-ALD lymphoblasts. Furthermore, X-ALD lymphoblasts produced higher levels of nitric oxide (NO) and cytokines (TNF-α and IL-1β); and treatment with NaPA, or lovastatin decreased the synthesis of NO. Our data indicates that X-ALD lymphoblasts are significantly affected by the accumulation of VLC fatty acids, which in turn induces changes in the cell membrane properties/functions that may play a role in the development/progression of the pathogenesis of X-ALD disease.

HDAC inhibitor SAHA normalizes the levels of VLCFAs in human skin fibroblasts from X-ALD patients and downregulates the expression of proinflammatory cytokines in Abcd1/2-silenced mouse astrocytes

“…The levels of C26:0 however, remained unchanged ( 31 ). Previous studies from our laboratory have shown that lovastatin, an inhibitor of HMG-CoA reductase and sodium phenyl acetate NAPA , can enhance VLCFA ␤ -oxidation and reduce VLCFA levels in human skin fi broblasts ( 32 ) and lymphoblasts ( 33 ) from X-ALD patients. Lovastatin also lowered the plasma levels of VLCFAs in X-ALD patients ( 34 ) and decreased the production of nitric oxide in X-ALD lymphoblasts ( 33 ).…”

“…Previous studies from our laboratory have shown that lovastatin, an inhibitor of HMG-CoA reductase and sodium phenyl acetate NAPA , can enhance VLCFA ␤ -oxidation and reduce VLCFA levels in human skin fi broblasts ( 32 ) and lymphoblasts ( 33 ) from X-ALD patients. Lovastatin also lowered the plasma levels of VLCFAs in X-ALD patients ( 34 ) and decreased the production of nitric oxide in X-ALD lymphoblasts ( 33 ). A number of other compounds, including 4-PBA ( 29 ), fenofibrate ( 25 ), and testosterone metabolites ( 35 ), have been shown to have the ability to lower VLCFA levels in X-ALD fibrobroblasts.…”

Very long-chain fatty acid accumulation causes lipotoxic response via 5-lipoxygenase in cerebral adrenoleukodystrophy

“…Oxidative burden has been reported to play a role in the pathobiology of X-ALD ( 7,8,14,17,38 ). We previously reported reduced levels of GSH in the plaque area of the cALD brain ( 39 ).…”

Peroxisomes in Humans: Metabolic Functions, Cross Talk with Other Organelles, and Pathophysiology of Peroxisomal Disorders

“…Furthermore, Vargas et al (2004) reported increased chemiluminescence and thiobarbituric acid reactive substances (TBARS) levels and decreased total antioxidant reactivity (TAR) in plasma from X-ALD patients. Oxidative damage has also been observed in fibroblasts (Fourcade et al 2008;Vargas et al 2004), plasma (Deon et al 2007;Rockenbach et al 2012), and lymphoblasts (Uto et al 2008) of X-ALD patients suggesting that the enhanced oxidative stress is systemic rather than localized. Moreover, Powers and co-workers reported oxidative modifications in post-mortem X-ALD brains with lipid peroxidation products predominantly present in the inflammatory demyelinative lesions and the adrenal cortex.…”