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

Abstract

This article is available online at http://www.jlr.org Supplementary key words peroxisome • very long chain FA • glia • nitric oxide • cytokine • suberoylanilide hydroxamic acid • X-adrenoleukodystrophy X-adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder, with an incidence of approximately 1:17,000 ( 1, 2 ). It is a postnatal progressive demyelinating disorder that primarily affects nervous system white matter and axons, the adrenal cortex, and testis ( 3-5 ). The biochemical signature of X-ALD is increased levels of saturated straight-chain very long chain FAs (VLCFAs; >22:0). VLCFA accumulates in all tissues and lipid classes; however, the degree of accumulation is higher in the cholesterol ester and sphingolipid fractions of brain white matter and adrenal cortex ( 6 ). The elevation of VLCFAs is the consequence of reduced VLCFA peroxisomal ␤ -oxidation ( 7 ) and/or increased activity of FA elongases ( 8, 9 ). The ALD gene (ABCD1), identifi ed by positional cloning ( 10 ), encodes a protein that is related to the peroxisomal ATP binding cassette (ABCD) transmembrane transporter proteins ( 11,12 ). The function of the adrenoleukodystrophy protein (ALDP) and its role in VLCFA metabolism and in the pathogenesis of X-ALD is not well understood at present. However, the VLCFA, especially C26:0, has been documented to cause metabolic alterations leading to membrane perturbation, redox imbalance ( 13 ), and changes in membrane lipid composition ( 14-18 ), as well as the induction of infl ammatory mediators in cultured astrocytes ( 19 ). This study was supported in part by grants from the National Institutes of Health (Grants NS-22576, NS-37766, C06 RR-018823, and C06 RR-015455, and VA merit award BX1072-01. Its Abbreviations: ALDP, adrenoleukodystrophy protein; ALDRP, adrenoleukodystrophy-related protein; AMN, adrenomyeloneuropathy; BBB, blood-brain barrier; cALD, cerebral adrenoleukodystrophy; FAME, FA methyl ester; HDAC, histone deacetylase; iNOS, inducible nitric oxide synthase; 5-LOX, 5-lipoxygenase; PA, phenylacetate; PBA, phenylbutyrate; ROS, reactive oxygen species; SAHA, suberoylanilide hydroxamic acid; TNF-␣ , tumor necrosis factor-␣ ; X-ALD, X-adrenoleukodystrophy; VLCFA, very long chain FA.

MicroRNA Profiling Identifies miR-196a as Differentially Expressed in Childhood Adrenoleukodystrophy and Adult Adrenomyeloneuropathy

“…The expression of ELOVL1 was measured following transfection of miR-196a mimic. There was no significant difference in levels of mRNA for ELOVL1 between U87 control and ABCD1-silenced astrocyte cells as well as between control and cALD fibroblasts as reported earlier in our studies [37] but there was significant decrease in the expression of ELOVL1 following transfection of miR-196a mimics in cALD fibroblasts and ABCD1-silenced U87 cells (Fig. 8a, c).…”

“…Silencing of ABCD1 in astrocytes and oligodendrocytes increased the VLCFA load and administration of HDAC inhibitor corrected the VLCFA load as well as the expression of proinflammatory cytokines in ABCD1-silenced astrocytes and proapoptotic proteins in ABCD1-silenced oligodendrocytes [37]. The observed downregulation of the expression of miR-196a following silencing of ABCD1 in astrocytes and SAHA-mediated reversal/upregulation of miR-196a in ABCD1-silenced U87 cells (Fig.…”

Combined treatment of adenosine nucleoside inhibitor NITD008 and histone deacetylase inhibitor vorinostat represents an immunotherapy strategy to ameliorate West Nile virus infection

“…Our previous in vitro studies demonstrated improvement in BBB disruption and neuronal injury using inhibitors of matrix metalloproteinase-9 and cyclooxygenase-2 and neutralizing antibodies against cytokines (Verma et al, 2010; Verma et al, 2011a). In this study, as compared to other HDAC inhibitors, such as Trichostatin A and MS-275, we chose SAHA as an anti-inflammatory drug to attenuate neuroinflammation because this drug can cross the BBB and has shown promise in treating inflammatory encephalopathy (Fang et al, 2014; Ge et al, 2013; Singh et al, 2011; Wang et al, 2013). SAHA treatment was reported to reduce the levels of pro-inflammatory cytokines, inducible nitric oxide and activation of NF-κB in activated mouse primary astrocytes (Singh et al, 2011).…”

“…In this study, as compared to other HDAC inhibitors, such as Trichostatin A and MS-275, we chose SAHA as an anti-inflammatory drug to attenuate neuroinflammation because this drug can cross the BBB and has shown promise in treating inflammatory encephalopathy (Fang et al, 2014; Ge et al, 2013; Singh et al, 2011; Wang et al, 2013). SAHA treatment was reported to reduce the levels of pro-inflammatory cytokines, inducible nitric oxide and activation of NF-κB in activated mouse primary astrocytes (Singh et al, 2011). Similarly, increased expression of HDAC6 was noted in mouse model of Alzheimer’s disease (AD), loss of which restored amyloid beta-associated cognitive deficits (Govindarajan et al, 2013).…”

Evaluation of Retinoids for Induction of the Redundant Gene ABCD2 as an Alternative Treatment Option in X-Linked Adrenoleukodystrophy

“…1) that sense the intracellular levels of steroid hormones and lipids including sterol regulatory element (SRE)-binding proteins (SREBPs), as well as nuclear receptors like the liver X receptor (LXR), thyroid hormone receptor (TR) and retinoid X receptor (RXR) [18]–[22]. In addition, the ABCD2 gene can be up-regulated by inhibitors of histone deacetylases (HDAC) like 4-phenylbutyrate and suberoylanilide hydroxamic acid (SAHA) [14], [23], indicating that also epigenetic mechanisms play a role in ABCD2 expression. Recently, also the T-cell factor 4 (TCF-4) and β-catenin, both of which are factors in the Wnt-signaling pathway regulating renewal and differentiation of hematopoietic stem cells, were shown to participate in ABCD2 regulation [24].…”