Prevention of 7-ketocholesterol-induced side effects by natural compounds

Abstract

Cholesterol oxidation products, also named oxysterols, can be formed either by cholesterol auto-oxidation, enzymatically or both. Among these oxysterols, 7-ketocholesterol (7KC) is mainly formed during radical attacks that take place on the carbon 7 of cholesterol. As increased levels of 7KC have been found in the tissues, plasma and/or cerebrospinal fluid of patients with major diseases, especially age-related diseases (cardiovascular diseases, eye diseases, neurodegenerative diseases), some cancers, and chronic inflammatory diseases, it is suspected that 7KC, could contribute to their development. Since 7KC, provided by the diet or endogenously formed, is not or little efficiently metabolized, except in hepatic cells, its cellular accumulation can trigger numerous side effects including oxidative stress, inflammation and cell death. To counteract 7KC-induced side effects, it is necessary to characterize the metabolic pathways activated by this oxysterol to identify potential targets for cytoprotection and geroprotection. Currently, several natural compounds (tocopherols, fatty acids, polyphenols, etc) or mixtures of compounds (oils) used in traditional medicine are able to inhibit the deleterious effects of 7KC. The different molecules identified could be valued in different ways (functional foods, recombinant molecules, theranostic) to prevent or treat diseases associated with 7KC.

Biotin attenuation of oxidative stress, mitochondrial dysfunction, lipid metabolism alteration and 7β-hydroxycholesterol-induced cell death in 158N murine oligodendrocytes

“…Our results support observations done in different cells exposed to other cytotoxic oxysterols (24(S)-hydroxycholesterol and 7 kC), which demonstrate that the alteration of cholesterol synthesis is associated with mitochondrial dysfunction leading different forms of cell death including apoptosis and necroptosis [51,92]. The alteration of cholesterol synthesis could contribute to the demyelination process and defects in the quality of myelin [29]. Cholesterol can also be oxidized, leading to the formation of 7 kC and 7b-OHC [93].…”

“…To oppose the deleterious effect of 7b-OHC, different strategies can be proposed, they can consist of either (i) degrading 7b-OHC and/or (ii) inactivating it via sulfonation or esterification with specific enzymes and/or (iii) inhibiting its signalling pathways leading to side effects with natural or synthetic molecules [29]. At the moment, a-tocopherol (the major component of vitamin E) and docosahexaenoic acid (DHA, C22:6 n-3) are the only molecules that can attenuate the noxious effects of 7b-OHC [24,30].…”

Lipids Nutrients in Parkinson and Alzheimer’s Diseases: Cell Death and Cytoprotection

“…Indeed, when their concentration is abnormal, oxysterols are associated with demyelinating or neurodegenerative diseases such as Parkinson's or Alzheimer's disease [108,109]. 7-ketocholesterol (7KC) is capable of inducing cell death and oxidative stress in 158N oligodendrocyte cells [110].…”

Localisation of oxysterols at the sub-cellular level and in biological fluids

“…This accumulation of oxysterols in myelin figures has been considered first as a phospholipidosis process to attenuate the cytotoxic effects of oxysterols. It is now suggested that these myelin figures could also include autophagic vesicles (resulting from reticulophagy) involving the fusion of the autophagosome, containing large parts of endoplasmic reticulum, within the lysosome [98]. It is suggested that the process of phospholipidosis would prevent the intracellular accumulation of 7KC which favours lysosomal membrane destabilization and contributes to cell death induction [97].…”