title: 7-Ketocholesterol is increased in the plasma of X-ALD patients and induces peroxisomal modifications in microglial cells: Potential roles of 7-ketocholesterol in the pathophysiology of X-ALD.
abstract: X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder induced by a mutation in the ABCD1 gene, which causes the accumulation of very long-chain fatty acids in tissue and plasma. Oxidative stress may be a hallmark of X-ALD. In the plasma of X-ALD patients with different forms of the disease, characterized by high levels of C24:0 and C26:0, we observed the presence of oxidative stress revealed by decreased levels of GSH, α-tocopherol, and docosahexaenoic acid (DHA). We showed that oxidative stress caused the oxidation of cholesterol and linoleic acid, leading to the formation of cholesterol oxide derivatives oxidized at C7 (7-ketocholesterol (7KC), 7β-hydroxycholesterol (7β-OHC), and 7α-hydroxycholesrol (7α-OHC)) and of 9- and 13-hydroxyoctadecadienoic acids (9-HODE, 13-HODE), respectively. High levels of 7KC, 7β-OHC, 7α-OHC, 9-HODE and 13-HODE were found. As 7KC induces oxidative stress, inflammation and cell death, which could play key roles in the development of X-ALD, the impact of 7KC on the peroxisomal status was determined in microglial BV-2 cells. Indeed, environmental stress factors such as 7KC could exacerbate peroxisomal dysfunctions in microglial cells and thus determine the progression of the disease. 7KC induces oxiapoptophagy in BV-2 cells: overproduction of H2O2and O2-, presence of cleaved caspase-3 and PARP, nuclear condensation and/or fragmentation; elevated [LC3-II/LC3-I] ratio, increased p62 levels. 7KC also induces several peroxisomal modifications: decreased Abcd1, Abcd2, Abcd3, Acox1 and/or Mfp2 mRNA and protein levels, increased catalase activity and decreased Acox1-activity. However, the Pex14 level was unchanged. It is suggested that high levels of 7KC in X-ALD patients could foster generalized peroxisomal dysfunction in microglial cells, which could in turn intensify brain damage.
authors.affiliation: Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism' EA 7270/Univ. Bourgogne Franche Comté/INSERM, Dijon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nury
authors.affiliation: Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism' EA 7270/Univ. Bourgogne Franche Comté/INSERM, Dijon, France; Univ. Monastir, Faculty of Medicine, LR12ES05, Lab-NAFS Nutrition - Functional Food & Vascular Health, Monastir, Tunisia; Univ. Sousse, Faculty of Medicine, Sousse, Tunisia.
authors.forename: Amira
authors.initials: A
authors.lastname: Zarrouk
authors.affiliation: SYSMEX, Department of Cytometry, Roissy, France.
authors.forename: Kévin
authors.initials: K
authors.lastname: Ragot
authors.affiliation: Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism' EA 7270/Univ. Bourgogne Franche Comté/INSERM, Dijon, France; Univ. Monastir, Faculty of Medicine, LR12ES05, Lab-NAFS Nutrition - Functional Food & Vascular Health, Monastir, Tunisia.
authors.forename: Meryam
authors.initials: M
authors.lastname: Debbabi
authors.affiliation: Centre Georges François Leclerc, Lab. Medical Biology, Dijon, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Riedinger
authors.affiliation: Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism' EA 7270/Univ. Bourgogne Franche Comté/INSERM, Dijon, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Vejux
authors.affiliation: INSERM UMR 1169, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Aubourg
authors.affiliation: Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism' EA 7270/Univ. Bourgogne Franche Comté/INSERM, Dijon, France. Electronic address: gerard.lizard@u-bourgogne.fr.
authors.forename: Gérard
authors.initials: G
authors.lastname: Lizard
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000097:blood; D042962:Acyl-CoA Oxidase / Q000097:blood; D000293:Adolescent; D000326:Adrenoleukodystrophy / Q000097:blood*; D000328:Adult; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000473:pathology; D016022:Case-Control Studies; D002374:Catalase / Q000378:metabolism; D002470:Cell Survival; D002648:Child; D018450:Disease Progression; D004281:Docosahexaenoic Acids / Q000737:chemistry; D005978:Glutathione / Q000737:chemistry; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D007653:Ketocholesterols / Q000097:blood* / Q000737:chemistry; D019787:Linoleic Acid / Q000737:chemistry; D008297:Male; D008565:Membrane Proteins / Q000097:blood / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000378:metabolism*; D008875:Middle Aged; D018384:Oxidative Stress; D020675:Peroxisomes / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000097:blood / Q000378:metabolism; D055815:Young Adult; D024502:alpha-Tocopherol / Q000737:chemistry
chemical_list: C063305:ABCD3 protein, human; D018528:ATP-Binding Cassette Transporters; D007653:Ketocholesterols; D008565:Membrane Proteins; C455539:PEX14 protein, human; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D004281:Docosahexaenoic Acids; D019787:Linoleic Acid; D006861:Hydrogen Peroxide; D002374:Catalase; D042962:Acyl-CoA Oxidase; D005978:Glutathione; D024502:alpha-Tocopherol; C003001:7-ketocholesterol
keywords: 7-Ketocholesterol; Microglial BV-2 cells; Peroxisome; Plasma; X-ALD biomarkers