期刊
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
卷 169, 期 -, 页码 123-136出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jsbmb.2016.03.037
关键词
Microglial BV-2 cells; 7-Ketocholesterol; Peroxisome; Plasma; X-ALD biomarkers
资金
- ELA (European Leukodystrophy Association) [2010-03014]
- Univ. Hospital of Dijon
- ASAD (Louhans, France)
- Department of Neurology (Univ. Hospital, Dijon, France)
- Association pour le Developpement des Sciences Neurologiques en Bourgogne (ADSNB, Dijon, France)
- Association Bourguignonne pour les Applications des Sciences de l'Information en Medecine (ABASIM, Dijon, France)
- Univ. Bourgogne
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, alpha-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), 7 beta-hydroxycholesterol (7 beta-OHC), and 7 alpha-hydroxycholesrol (7 alpha-OHC)) and of 9- and 13-hydroxyoctadecadienoic acids (9-HODE, 13-HODE), respectively. High levels of 7KC, 7 beta-OHC, 7 alpha-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 H2O2 and O-2, presence of cleaved caspase-3 and PARR nuclear condensation and/or fragmentation; elevated [LC3-II/LC3-11 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. (C) 2016 Elsevier Ltd. All rights reserved.
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