6533b81ffe1ef96bd1276ea6

RESEARCH PRODUCT

modifications peroxysomales associées à l'oxyapoptophagie induite par le 7-cétocholestérol et identification de lipides cytoprotecteurs

subject

description

Oxidative stress is often increased in several diseases such as age-related diseases (cardiovascular diseases, eye diseases (age-related macular degeneration (AMD) and cataracts), neurodegenerative diseases (Alzheimer's disease, multiple sclerosis), chronic inflammatory diseases (chronic inflammatory bowel disease (IBD)) as well as certain rare genetic diseases (Niemann Pick's disease, X-linked adrenoleukodystrophy (X-ALD)). Oxidative stress can oxidize various molecules, in particular the cholesterol present in lipid membranes, and lead to the formation of oxidized cholesterol derivatives: oxysterols. Some of them, such as 7-ketocholesterol (7KC), are toxic and may be the cause of a type of cell death, oxiapoptophagy, associating an increase in oxidative stress, activation of apoptosis and autophagic criteria. Using 158N murine oligodendrocytes, this work has allowed to better characterize the oxiapoptophagy induced by 7KC. The toxicity of 7KC on cellular organelles such as mitochondria and lysosome was confirmed. This work also shows that oxyapoptophagy is associated with topographic, morphological and functional modifications of the peroxisome. It has been shown that 7KC induces a decrease in the expression and activity of certain peroxisomal transporters (ABCD1, ABCD3) and peroxisomal enzymes (ACOX1, MFP2, catalase) and promotes an accumulation of very long-chain fatty acids (C24:0, C24:1 and C26:0, C26:1) degraded in the peroxisome. It has also been shown that certain lipids (α-tocopherol, α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), oleic acid (AO), Lorenzo's oil (oleic acid + erucic acid (4: 1)) and sulfo-N-succinimdyl oleate (SSO)) are cytoprotective and strongly attenuate 7KC-induced oxyaptophagy. This makes it possible to envisage the prevention or treatment of diseases associated with high levels of 7KC, in particular certain age-related diseases for which there are no effective treatments.