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• W2103265666 abstract "X-adrenoleukodystrophy (X-ALD) is a peroxisomal metabolic disorder caused by mutations in the ABCD1 gene encoding the peroxisomal ABC transporter adrenoleukodystrophy protein (ALDP). The consistent metabolic abnormality in all forms of X-ALD is an inherited defect in the peroxisomal β-oxidation of very long chain FAs (VLCFAs >C22:0) and the resultant pathognomic accumulation of VLCFA. The accumulation of VLCFA leads to a neuroinflammatory disease process associated with demyelination of the cerebral white matter. The present study underlines the importance of a potent histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA) in inducing the expression of ABCD2 [adrenoleukodystrophy-related protein (ALDRP)], and normalizing the peroxisomal β-oxidation, as well as the saturated and monounsaturated VLCFAs in cultured human skin fibroblasts of X-ALD patients. The expression of ELOVL1, the single elongase catalyzing the synthesis of both saturated VLCFA (C26:0) and monounsaturated VLCFA (C26:1), was also reduced by SAHA treatment. In addition, using Abcd1/Abcd2-silenced mouse primary astrocytes, we also examined the effects of SAHA in VLCFA-induced inflammatory response. SAHA treatment decreased the inflammatory response as expression of inducible nitric oxide synthase, inflammatory cytokine, and activation of NF-κB in Abcd1/Abcd2-silenced mouse primary astrocytes was reduced. These observations indicate that SAHA corrects both the metabolic disease of VLCFA as well as secondary inflammatory disease; therefore, it may be an ideal drug candidate to be tested for X-ALD therapy in humans X-adrenoleukodystrophy (X-ALD) is a peroxisomal metabolic disorder caused by mutations in the ABCD1 gene encoding the peroxisomal ABC transporter adrenoleukodystrophy protein (ALDP). The consistent metabolic abnormality in all forms of X-ALD is an inherited defect in the peroxisomal β-oxidation of very long chain FAs (VLCFAs >C22:0) and the resultant pathognomic accumulation of VLCFA. The accumulation of VLCFA leads to a neuroinflammatory disease process associated with demyelination of the cerebral white matter. The present study underlines the importance of a potent histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA) in inducing the expression of ABCD2 [adrenoleukodystrophy-related protein (ALDRP)], and normalizing the peroxisomal β-oxidation, as well as the saturated and monounsaturated VLCFAs in cultured human skin fibroblasts of X-ALD patients. The expression of ELOVL1, the single elongase catalyzing the synthesis of both saturated VLCFA (C26:0) and monounsaturated VLCFA (C26:1), was also reduced by SAHA treatment. In addition, using Abcd1/Abcd2-silenced mouse primary astrocytes, we also examined the effects of SAHA in VLCFA-induced inflammatory response. SAHA treatment decreased the inflammatory response as expression of inducible nitric oxide synthase, inflammatory cytokine, and activation of NF-κB in Abcd1/Abcd2-silenced mouse primary astrocytes was reduced. These observations indicate that SAHA corrects both the metabolic disease of VLCFA as well as secondary inflammatory disease; therefore, it may be an ideal drug candidate to be tested for X-ALD therapy in humans X-adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder, with an incidence of approximately 1:17,000 (1Bezman L. Moser A.B. Raymond G.V. Rinaldo P. Watkins P.A. Smith K.D. Kass N.E. Moser H.W. Adrenoleukodystrophy: incidence, new mutation rate, and results of extended family screening.Ann. Neurol. 2001; 49: 512-517Crossref PubMed Scopus (266) Google Scholar, 2Dubois-Dalcq M. Feigenbaum V. Aubourg P. The neurobiology of X-linked adrenoleukodystrophy, a demyelinating peroxisomal disorder.Trends Neurosci. 1999; 22: 4-12Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). It is a postnatal progressive demyelinating disorder that primarily affects nervous system white matter and axons, the adrenal cortex, and testis (3Moser H.W. Therapy of X-linked adrenoleukodystrophy.NeuroRx. 2006; 3: 246-253Crossref PubMed Scopus (47) Google Scholar, 4Singh I. Biochemistry of peroxisomes in health and disease.Mol. Cell. Biochem. 1997; 167: 1-29Crossref PubMed Scopus (134) Google Scholar, 5Singh I. Pujol A. Pathomechanisms underlying X-adrenoleukodystrophy: a three-hit hypothesis.Brain Pathol. 2010; 20: 838-844Crossref PubMed Scopus (94) Google Scholar). 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 (6Moser H.W. Loes D.J. Melhem E.R. Raymond G.V. Bezman L. Cox C.S. Lu S.E. X-linked adrenoleukodystrophy: overview and prognosis as a function of age and brain magnetic resonance imaging abnormality. A study involving 372 patients.Neuropediatrics. 2000; 31: 227-239Crossref PubMed Scopus (153) Google Scholar). The elevation of VLCFAs is the consequence of reduced VLCFA peroxisomal β-oxidation (7Singh I. Moser A.E. Goldfischer S. Moser H.W. Lignoceric acid is oxidized in the peroxisome: implications for the Zellweger cerebro-hepato-renal syndrome and adrenoleukodystrophy.Proc. Natl. Acad. Sci. USA. 1984; 81: 4203-4207Crossref PubMed Scopus (330) Google Scholar) and/or increased activity of FA elongases (8Kemp S. Valianpour F. Denis S. Ofman R. Sanders R.J. Mooyer P. Barth P.G. Wanders R.J. Elongation of very long-chain fatty acids is enhanced in X-linked adrenoleukodystrophy.Mol. Genet. Metab. 2005; 84: 144-151Crossref PubMed Scopus (72) Google Scholar, 9Koike R. Tsuji S. Ohno T. Suzuki Y. Orii T. Miyatake T. Physiological significance of fatty acid elongation system in adrenoleukodystrophy.J. Neurol. Sci. 1991; 103: 188-194Abstract Full Text PDF PubMed Scopus (30) Google Scholar). The ALD gene (ABCD1), identified by positional cloning (10Moser H.W. Lorenzo oil therapy for adrenoleukodystrophy: a prematurely amplified hope.Ann. Neurol. 1993; 34: 121-122Crossref PubMed Scopus (26) Google Scholar), encodes a protein that is related to the peroxisomal ATP binding cassette (ABCD) transmembrane transporter proteins (11Contreras M. Mosser J. Mandel J.L. Aubourg P. Singh I. The protein coded by the X-adrenoleukodystrophy gene is a peroxisomal integral membrane protein.FEBS Lett. 1994; 344: 211-215Crossref PubMed Scopus (63) Google Scholar, 12Contreras M. Sengupta T.K. Sheikh F. Aubourg P. Singh I. Topology of ATP-binding domain of adrenoleukodystrophy gene product in peroxisomes.Arch. Biochem. Biophys. 1996; 334: 369-379Crossref PubMed Scopus (44) Google Scholar). 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 (13Khan M. Singh J. Singh I. Plasmalogen deficiency in cerebral adrenoleukodystrophy and its modulation by lovastatin.J. Neurochem. 2008; 106: 1766-1779PubMed Google Scholar), and changes in membrane lipid composition (14Di Biase A. Di Benedetto R. Fiorentini C. Travaglione S. Salvati S. Attorri L. Pietraforte D. Free radical release in C6 glial cells enriched in hexacosanoic acid: implication for X-linked adrenoleukodystrophy pathogenesis.Neurochem. Int. 2004; 44: 215-221Crossref PubMed Scopus (22) Google Scholar, 15Fourcade S. Lopez-Erauskin J. Galino J. Duval C. Naudi A. Jove M. Kemp S. Villarroya F. Ferrer I. Pamplona R. et al.Early oxidative damage underlying neurodegeneration in X-adrenoleukodystrophy.Hum. Mol. Genet. 2008; 17: 1762-1773Crossref PubMed Scopus (158) Google Scholar, 16Hein S. Schonfeld P. Kahlert S. Reiser G. Toxic effects of X-linked adrenoleukodystrophy-associated, very long chain fatty acids on glial cells and neurons from rat hippocampus in culture.Hum. Mol. Genet. 2008; 17: 1750-1761Crossref PubMed Scopus (113) Google Scholar, 17Ho J.K. Moser H. Kishimoto Y. Hamilton J.A. Interactions of a very long chain fatty acid with model membranes and serum albumin. Implications for the pathogenesis of adrenoleukodystrophy.J. Clin. Invest. 1995; 96: 1455-1463Crossref PubMed Scopus (165) Google Scholar, 18Khan M. Singh J. Gilg A.G. Uto T. Singh I. Very long-chain fatty acid accumulation causes lipotoxic response via 5-lipoxygenase in cerebral adrenoleukodystrophy.J. Lipid Res. 2010; 51: 1685-1695Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar), as well as the induction of inflammatory mediators in cultured astrocytes (19Singh J. Khan M. Singh I. Silencing of Abcd1 and Abcd2 genes sensitizes astrocytes for inflammation: implication for X-adrenoleukodystrophy.J. Lipid Res. 2009; 50: 135-147Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). At present, there is no satisfactory therapy for X-ALD. Reduction of VLCFA may be an ideal approach, but then none of the reported agents significantly decrease the levels of VLCFA in human brain. Other approaches, such as hematopoietic stem cell transplantation and lentiviral-vector-associated gene therapy, have shown clinical benefits (20Shapiro E. Krivit W. Lockman L. Jambaque I. Peters C. Cowan M. Harris R. Blanche S. Bordigoni P. Loes D. et al.Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy.Lancet. 2000; 356: 713-718Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar). They, however, are effective only in patients with the earliest stage of cerebral adrenoleukodystrophy (cALD). Thus, finding a treatment for X-ALD remains a challenge. Recent studies on neuroinflammation using histone deacetylase (HDAC) inhibitors show potential to ameliorate metabolic defects in neurological disorders, including (21Brichta L. Hofmann Y. Hahnen E. Siebzehnrubl F.A. Raschke H. Blumcke I. Eyupoglu I.Y. Wirth B. Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy.Hum. Mol. Genet. 2003; 12: 2481-2489Crossref PubMed Scopus (327) Google Scholar, 22Hahnen E. Eyupoglu I.Y. Brichta L. Haastert K. Trankle C. Siebzehnrubl F.A. Riessland M. Holker I. Claus P. Romstock J. et al.In vitro and ex vivo evaluation of second-generation histone deacetylase inhibitors for the treatment of spinal muscular atrophy.J. Neurochem. 2006; 98: 193-202Crossref PubMed Scopus (134) Google Scholar) compromised gene metabolic disorders, by the activation of the overlapping function of the redundant gene. Pharmacological therapy for X-ALD remains attractive because of its potential to be effective pre- as well as postnatally. Various lines of evidence suggest that pharmacological induction of ABCD2 and/or ABCD3 may represent a therapeutic strategy for X-ALD. ABCD2, the closest homolog of ABCD1 (23Holzinger A. Kammerer S. Berger J. Roscher A.A. cDNA cloning and mRNA expression of the human adrenoleukodystrophy related protein (ALDRP), a peroxisomal ABC transporter.Biochem. Biophys. Res. Commun. 1997; 239: 261-264Crossref PubMed Scopus (73) Google Scholar), and ABCD3 (24Holzinger A. Kammerer S. Roscher A.A. Primary structure of human PMP69, a putative peroxisomal ABC-transporter.Biochem. Biophys. Res. Commun. 1997; 237: 152-157Crossref PubMed Scopus (80) Google Scholar) can compensate for β-oxidation defects in X-ALD fibroblasts when overexpressed (25Netik A. Forss-Petter S. Holzinger A. Molzer B. Unterrainer G. Berger J. Adrenoleukodystrophy-related protein can compensate functionally for adrenoleukodystrophy protein deficiency (X-ALD): implications for therapy.Hum. Mol. Genet. 1999; 8: 907-913Crossref PubMed Scopus (120) Google Scholar). Furthermore, the biochemical abnormalities found in Abcd1-knockout mice can be restored by overexpression of Abcd2 (26Pujol A. Ferrer I. Camps C. Metzger E. Hindelang C. Callizot N. Ruiz M. Pampols T. Giros M. Mandel J.L. Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: a therapeutic target for X-adrenoleukodystrophy.Hum. Mol. Genet. 2004; 13: 2997-3006Crossref PubMed Scopus (154) Google Scholar). A key role of protein lysine acetylation in metabolic regulation was recently shown, in which virtually every enzyme of the FA oxidation pathways was found to be acetylated (27Zhao S. Xu W. Jiang W. Yu W. Lin Y. Zhang T. Yao J. Zhou L. Zeng Y. Li H. et al.Regulation of cellular metabolism by protein lysine acetylation.Science. 2010; 327: 1000-1004Crossref PubMed Scopus (1466) Google Scholar). HDAC-inhibitory activity (28Gondcaille C. Depreter M. Fourcade S. Lecca M.R. Leclercq S. Martin P.G. Pineau T. Cadepond F. ElEtr M. Bertrand N. et al.Phenylbutyrate up-regulates the adrenoleukodystrophy-related gene as a nonclassical peroxisome proliferator.J. Cell Biol. 2005; 169: 93-104Crossref PubMed Scopus (59) Google Scholar) of 4-phenyl butyrate (4-PBA) was associated with induction of ABCD2 expression in Abcd1-knockout mice. This induction resulted in reduced levels of VLCFA in brain and adrenal glands (29Kemp S. Wei H.M. Lu J.F. Braiterman L.T. McGuinness M.C. Moser A.B. Watkins P.A. Smith K.D. Gene redundancy and pharmacological gene therapy: implications for X-linked adrenoleukodystrophy.Nat. Med. 1998; 4: 1261-1268Crossref PubMed Scopus (208) Google Scholar). Surprisingly, no ABCD2 induction or VLCFA correction was observed in adrenomyeloneuropathy (AMN) patients (30Kemp S. Wanders R.J. X-linked adrenoleukodystrophy: very long-chain fatty acid metabolism, ABC half-transporters and the complicated route to treatment.Mol. Genet. Metab. 2007; 90: 268-276Crossref PubMed Scopus (65) Google Scholar) with 4-PBA therapy. Valproic acid, a nonselective HDAC inhibitor, was recently shown to induce ABCD2 expression and correction of oxidative damage in a mouse X-ALD model and in peripheral blood mononuclear cells from X-ALD patients (31Fourcade S. Ruiz M. Guilera C. Hahnen E. Brichta L. Naudi A. Portero-Otin M. Dacremont G. Cartier N. Wanders R. et al.Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy.Hum. Mol. Genet. 2010; 19: 2005-2014Crossref PubMed Scopus (78) Google Scholar). The levels of C26:0 however, remained unchanged (31Fourcade S. Ruiz M. Guilera C. Hahnen E. Brichta L. Naudi A. Portero-Otin M. Dacremont G. Cartier N. Wanders R. et al.Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy.Hum. Mol. Genet. 2010; 19: 2005-2014Crossref PubMed Scopus (78) Google Scholar). Previous studies from our laboratory have shown that lovastatin, an inhibitor of HMG-CoA reductase and sodium phenyl acetate NAPA, can enhance VLCFA β-oxidation and reduce VLCFA levels in human skin fibroblasts (32Singh I. Khan M. Key L. Pai S. Lovastatin for X-linked adrenoleukodystrophy.N. Engl. J. Med. 1998; 339: 702-703Crossref PubMed Scopus (84) Google Scholar) and lymphoblasts (33Uto T. Contreras M.A. Gilg A.G. Singh I. Oxidative imbalance in nonstimulated X-adrenoleukodystrophy-derived lymphoblasts.Dev. Neurosci. 2008; 30: 410-418Crossref PubMed Scopus (35) Google Scholar) from X-ALD patients. Lovastatin also lowered the plasma levels of VLCFAs in X-ALD patients (34Pai G.S. Khan M. Barbosa E. Key L.L. Craver J.R. Cure J.K. Betros R. Singh I. Lovastatin therapy for X-linked adrenoleukodystrophy: clinical and biochemical observations on 12 patients.Mol. Genet. Metab. 2000; 69: 312-322Crossref PubMed Scopus (59) Google Scholar) and decreased the production of nitric oxide in X-ALD lymphoblasts (33Uto T. Contreras M.A. Gilg A.G. Singh I. Oxidative imbalance in nonstimulated X-adrenoleukodystrophy-derived lymphoblasts.Dev. Neurosci. 2008; 30: 410-418Crossref PubMed Scopus (35) Google Scholar). A number of other compounds, including 4-PBA (29Kemp S. Wei H.M. Lu J.F. Braiterman L.T. McGuinness M.C. Moser A.B. Watkins P.A. Smith K.D. Gene redundancy and pharmacological gene therapy: implications for X-linked adrenoleukodystrophy.Nat. Med. 1998; 4: 1261-1268Crossref PubMed Scopus (208) Google Scholar), fenofibrate (25Netik A. Forss-Petter S. Holzinger A. Molzer B. Unterrainer G. Berger J. Adrenoleukodystrophy-related protein can compensate functionally for adrenoleukodystrophy protein deficiency (X-ALD): implications for therapy.Hum. Mol. Genet. 1999; 8: 907-913Crossref PubMed Scopus (120) Google Scholar), and testosterone metabolites (35Petroni A. Cappa M. Carissimi R. Blasevich M. Uziel G. Effect of testosterone metabolites on ABC half-transporter relative gene expression in X-linked adrenoleukodystrophy.J. Inherit. Metab. Dis. 2007; 30: 828Crossref PubMed Scopus (4) Google Scholar), have been shown to have the ability to lower VLCFA levels in X-ALD fibrobroblasts. However, none of the compounds to date have shown the ability to halt neurodegenerative progression. Perturbation in acetylation homeostasis is emerging as a central event in the pathogenesis of neurodegeneration (36Saha R.N. Pahan K. HATs and HDACs in neurodegeneration: a tale of disconcerted acetylation homeostasis.Cell Death Differ. 2006; 13: 539-550Crossref PubMed Scopus (320) Google Scholar). Hence, recent studies have indicated that HDAC inhibitors might prove useful in treatment of such neurodegenerative disorders as Huntington’s Disease (37Ferrante R.J. Kubilus J.K. Lee J. Ryu H. Beesen A. Zucker B. Smith K. Kowall N.W. Ratan R.R. Luthi-Carter R. et al.Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington’s disease mice.J. Neurosci. 2003; 23: 9418-9427Crossref PubMed Google Scholar, 38Gardian G. Browne S.E. Choi D.K. Klivenyi P. Gregorio J. Kubilus J.K. Ryu H. Langley B. Ratan R.R. Ferrante R.J. et al.Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic mouse model of Huntington’s disease.J. Biol. Chem. 2005; 280: 556-563Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar, 39Hockly E. Richon V.M. Woodman B. Smith D.L. Zhou X. Rosa E. Sathasivam K. Ghazi-Noori S. Mahal A. Lowden P.A. et al.Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington’s disease.Proc. Natl. Acad. Sci. USA. 2003; 100: 2041-2046Crossref PubMed Scopus (748) Google Scholar), spinal muscular atrophy (40Chang J.G. Hsieh-Li H.M. Jong Y.J. Wang N.M. Tsai C.H. Li H. Treatment of spinal muscular atrophy by sodium butyrate.Proc. Natl. Acad. Sci. USA. 2001; 98: 9808-9813Crossref PubMed Scopus (355) Google Scholar), amyotrophic lateral sclerosis (41Corcoran L.J. Mitchison T.J. Liu Q. A novel action of histone deacetylase inhibitors in a protein aggresome disease model.Curr. Biol. 2004; 14: 488-492Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 42Petri S. Kiaei M. Kipiani K. Chen J. Calingasan N.Y. Crow J.P. Beal M.F. Additive neuroprotective effects of a histone deacetylase inhibitor and a catalytic antioxidant in a transgenic mouse model of amyotrophic lateral sclerosis.Neurobiol. Dis. 2006; 22: 40-49Crossref PubMed Scopus (148) Google Scholar, 43Ryu H. Smith K. Camelo S.I. Carreras I. Lee J. Iglesias A.H. Dangond F. Cormier K.A. Cudkowicz M.E. Brown Jr., R.H. et al.Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice.J. Neurochem. 2005; 93: 1087-1098Crossref PubMed Scopus (272) Google Scholar), and experimental autoimmune encephalomyelitis (44Camelo S. Iglesias A.H. Hwang D. Due B. Ryu H. Smith K. Gray S.G. Imitola J. Duran G. Assaf B. et al.Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis.J. Neuroimmunol. 2005; 164: 10-21Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar). Amelioration of neurodegenerative conditions such as oxidative stress (45Ryu H. Lee J. Olofsson B.A. Mwidau A. Dedeoglu A. Escudero M. Flemington E. Azizkhan-Clifford J. Ferrante R.J. Ratan R.R. Histone deacetylase inhibitors prevent oxidative neuronal death independent of expanded polyglutamine repeats via an Sp1-dependent pathway.Proc. Natl. Acad. Sci. USA. 2003; 100: 4281-4286Crossref PubMed Scopus (221) Google Scholar), and preservation of white matter structure and function (46Baltan S. Murphy S.P. Danilov C.A. Bachleda A. Morrison R.S. Histone deacetylase inhibitors preserve white matter structure and function during ischemia by conserving ATP and reducing excitotoxicity.J. Neurosci. 2011; 31: 3990-3999Crossref PubMed Scopus (95) Google Scholar) by HDAC inhibitors strongly point toward acetylation-dependent mechanisms in demyelination and neurodegeneration. Although treatment of cancer has been the primary target for the clinical development of HDAC inhibitors, administration of HDAC inhibitors has also shown beneficial effects in some noncancer disorders, such as sickle cell anemia, muscular dystrophy, neurodegenerative diseases, and inflammatory disorders (47Wiech N.L. Fisher J.F. Helquist P. Wiest O. Inhibition of histone deacetylases: a pharmacological approach to the treatment of non-cancer disorders.Curr. Top. Med. Chem. 2009; 9: 257-271Crossref PubMed Scopus (67) Google Scholar). Among the various classes tested, suberoylanilide hydroxamic acid (SAHA) was reported as the most promising therapeutic agent for treatment of spinal muscular atrophy (SMA) due to its ability to substantially increase survival motor neuron (SMN) protein levels at low micromolar concentration and completely inhibit HDAC activity. The present study demonstrates that treatment with the potent and selective HDAC inhibitor SAHA (48Göttlicher M. Minucci S. Zhu P. Kramer O.H. Schimpf A. Giavara S. Sleeman J.P. Lo Coco F. Nervi C. Pelicci P.G. et al.Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells.EMBO J. 2001; 20: 6969-6978Crossref PubMed Scopus (1568) Google Scholar, 49Phiel C.J. Zhang F. Huang E.Y. Guenther M.G. Lazar M.A. Klein P.S. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen.J. Biol. Chem. 2001; 276: 36734-36741Abstract Full Text Full Text PDF PubMed Scopus (1475) Google Scholar) normalized the levels of VLCFA in skin fibroblasts from X-ALD patients by increasing the peroxisomal β-oxidation activity. SAHA also inhibited the induction of proinflammatory cytokines and inducible nitric oxide synthase (iNOS) in astrocytes silenced for Abcd1/2. Because SAHA crosses the blood-brain barrier (BBB), increases acetylation in brain (39Hockly E. Richon V.M. Woodman B. Smith D.L. Zhou X. Rosa E. Sathasivam K. Ghazi-Noori S. Mahal A. Lowden P.A. et al.Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington’s disease.Proc. Natl. Acad. Sci. USA. 2003; 100: 2041-2046Crossref PubMed Scopus (748) Google Scholar), and reduces neuroinflammation, we propose that this drug may have therapeutic potential to ameliorate the X-ALD disease process. DMEM and HBSS were purchased from Invitrogen Life Technologies; FBS was purchased from BioAbChem, Inc. (Ladson, SC). ALDP antibody was from Chemicon International, Inc. (Temecula, CA). Adrenoleukodystrophy-related protein (ALDRP) antibody was custom-made from ANASPEC against the mouse 20-residue c-terminal sequence: 722 CKILGEDSVLKTIQTPEKTS 741. 5-Lipoxygenase (5-LOX) antibody was purchased from Cayman Chemical (Ann Arbor, MI). Na+K+ATPase antibody was purchased from Santa Cruz Biotechnology (Santa Cruz, CA). ECL and nitrocellulose membranes were purchased from Amersham Biosciences. FA methyl ester (FAME) standards were obtained from Supelco (Bellefonte, PA). [l-14C]lignoceric acid was prepared as described previously (50Hoshi M. Kishimoto Y. Synthesis of cerebronic acid from lignoceric acid by rat brain preparation. Some properties and distribution of the -hydroxylation system.J. Biol. Chem. 1973; 248: 4123-4130Abstract Full Text PDF PubMed Google Scholar). [1-14C]palmitic acid and 125I-labeled protein A were obtained from ICN (Cleveland, OH). Human skin fibroblasts derived from normal (control; GM03348), X-ALD (GM04932, GM04934, and GM04904), and AMN (GM07531) patients, and were obtained from the National Institute of General Medical Sciences (NIGMS) Human Genetic Mutant Cell Repository at the Coriell Institute for Medical Research (ccr.coriell.org/). The fibroblasts were cultured in DMEM containing 10% FBS and antibiotic/antimicotic. C57BL6 mice from Jackson Laboratory (Bar Harbor, ME) were maintained at the Medical University of South Carolina (MUSC) animal facility. All animal procedures were approved by the MUSC Animal Review Committee, and all animals received humane care in compliance with the MUSC experimental guidelines and the National Research Council’s criteria for humane care (Guide for Care and Use of Laboratory Animals). Primary astrocyte-enriched cultures were prepared from the whole cortex of 1 day-old C57BL/6 mice as described previously (51Pahan K. Sheikh F.G. Khan M. Namboodiri A.M. Singh I. Sphingomyelinase and ceramide stimulate the expression of inducible nitric-oxide synthase in rat primary astrocytes.J. Biol. Chem. 1998; 273: 2591-2600Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar). All cultured cells were maintained at 37°C in 5% CO2. The Silencer siRNA (Ambion; Austin, TX) was used for Abcd1 and Abcd2 silencing in primary mouse astrocytes as described previously (19Singh J. Khan M. Singh I. Silencing of Abcd1 and Abcd2 genes sensitizes astrocytes for inflammation: implication for X-adrenoleukodystrophy.J. Lipid Res. 2009; 50: 135-147Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). The siRNAs were mixed and diluted in OPTI-MEM1 medium to a final concentration of 30 nM/well. A negative control with sequence similarity to no known human, mouse, or rat gene was included. Cells were maintained in DMEM with reduced serum (2%). Silencing was observed with Western blot and mRNA quantification. Forty-eight hours after silencing for Abcd-1/2, cells were treated with SAHA and harvested 72 h later for protein and RNA analysis. For protein analysis of the transfected cells, three wells per plate were lysed and used for protein measurements and protein levels (Western blot). Cells were maintained for 6 days in DMEM with 2% FBS before harvesting for the analysis. A pool of three siRNAs for human ABCD2 was purchased from Santa Cruz Biotechnology (Santa Cruz, CA) and was used to transfect X-ALD fibroblasts at final concentration of 2 μM. Forty-eight hours after silencing for ABCD2, cells were treated with SAHA for 3 days with fresh addition of medium/SAHA every day. The peroxisomal oxidation of FAs in control, X-ALD fibroblasts, and SAHA-treated X-ALD fibroblasts was determined in 6-well plates as described previously (19Singh J. Khan M. Singh I. Silencing of Abcd1 and Abcd2 genes sensitizes astrocytes for inflammation: implication for X-adrenoleukodystrophy.J. Lipid Res. 2009; 50: 135-147Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). β-Oxidation of FAs to acetate (water-soluble product) was determined using [1-14C]-labeled FAs as substrate (C24:0, lignoceric acid, or C16:0, palmitic acid) (American Radiolabeled Co.; St. Louis, MO), as described previously (52Singh I. Paintlia A.S. Khan M. Stanislaus R. Paintlia M.K. Haq E. Singh A.K. Contreras M.A. Impaired peroxisomal function in the central nervous system with inflammatory disease of experimental autoimmune encephalomyelitis animals and protection by lovastatin treatment.Brain Res. 2004; 1022: 1-11Crossref PubMed Scopus (55) Google Scholar). Cells grown in parallel in the same plate were used to determine the protein present in the assays. Experiments were performed in triplicate. Total lipids were extracted from control and treated cells as described previously (53Wilson R. Sargent J.R. Lipid and fatty acid composition of brain tissue from adrenoleukodystrophy patients.J. Neurochem. 1993; 61: 290-297Crossref PubMed Scopus (47) Google Scholar). The FAMEs were analyzed by GC (Shimadzu chromatograph GC-15A attached to a Shimadzu chromatopac C-R3A integrator) using a fused silica capillary column (25 M 007 series methyl silicone, 0.25 mm internal diameter, 0.25 μm film thickness) from Quadrex Corporation (Woodbridge, CT) in a gas chromatograph GC-17A connected with a flame ionization detector from Shimadzu Corporation. Then, 40 μg of total cellular protein was resolved by electrophoresis on 4–20% polyacrylamide gels. After incubation with antiserum raised against mice ALDP, ALDRP, 5-LOX, p65, Na+K+ATPase, and iNOS, the membranes were then incubated with HRP-conjugated anti-rabbit or mouse IgG for 1 h. The membranes were detected by autoradiography using ECL-plus (Amersham Biosciences) after washing with TBST buffer. Following total RNA extraction using TRIzol (Invitrogen) per the manufacturer’s protocol, single-stranded cDNA was synthesized from total RNA as described previously (19Singh J. Khan M. Singh I. Silencing of Abcd1 and Abcd2 genes sensitizes astrocytes for inflammation: implication for X-adrenoleukodystrophy.J. Lipid Res. 2009; 50: 135-147Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). Real-time PCR was conducted using the Bio-Rad iCycler (iCycler iQ Multi-Color Real Time PCR Detection System; Bio-Rad). The primer sets for use were designed (Oligoperfect™ designer, Invitrogen) and synthesized from Integrated DNA Technologies (Coralville, IA). The primer sequences for mouse tumor necrosis factor-α (TNF-α) were: FP 5′-ctt ctg tct act gaa ctt cgg ggt-3′, RP 5′-tgg aac tga tga gag gga gcc-3′; glyceraldehyde-3-phosphate dehydrogenase FP, 5′-cct acc ccc aat gta tcc gtt gtg-3′; RP-5′-gga gga atg gga gtt gct gtt gaa-3′, iNOS FP 5′-gga aga gga aca act act gct ggt-3′, RP 5′-gaa ctg agg g" @default.
• W2103265666 created "2016-06-24" @default.
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• W2103265666 date "2011-11-01" @default.
• W2103265666 modified "2023-09-25" @default.
• W2103265666 title "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" @default.
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