7-Ketocholesterol Incorporation into Sphingolipid/Cholesterol-enriched (Lipid Raft) Domains Is Impaired by Vitamin E

Abstract

Cholesterol oxides, in particular 7-ketocholesterol, are proatherogenic compounds that induce cell death in the vascular wall when localized in lipid raft domains of the cell membrane. Deleterious effects of 7-ketocholesterol can be prevented by vitamin E, but the molecular mechanism involved is unclear. In this study, unlike ␥-tocopherol, the ␣-tocopherol vitamin E form was found to prevent 7-ketocholesterol-mediated apoptosis of A7R5 smooth muscle cells. To be operative, ␣-tocopherol needed to be added to the cells before 7-ketocholesterol, and its anti-apoptotic effect was reduced and even suppressed when added together or after 7-ketocholesterol, respectively. Both pre-and co-treatment of the cells with ␣-tocopherol resulted in the redistribution of 7-ketocholesterol out of the sphingolipid/cholesterol-enriched (lipid raft) domains. In turn, fewer amounts of ␣-tocopherol associated with lipid rafts on 7-ketocholesterol-pretreated cells compared with untreated cells, with no prevention of cell death in this case. In further support of the implication of lipid raft domains, the dephosphorylation/inactivation of Akt-PKB was involved in the 7-ketocholesterol-induced apoptosis. Akt-PKB dephosphorylation was prevented by ␣-tocopherol, but not ␥-tocopherol pretreatment.

24(S)-Hydroxycholesterol Induces Neuronal Cell Death through Necroptosis, a Form of Programmed Necrosis

“…The absence of typical apoptotic features in 24S-OHC-treated cells also supports the involvement of programmed necrosis. It has been known that oxysterols such as 7-ketocholesterol can induce apoptotic cell death through association with membrane lipid raft domains (15,32). We observed typical apoptotic features such as PS exposure and caspase activation in SH-SY5Y cells that were treated with 7-ketocholesterol (data not shown), suggesting that 7-ketocholesterol induces cell death via a different pathway with 24S-OHC.…”

“…It has also been shown that 24S-OHC acts as a ligand of the nuclear receptor liver X receptor, which regulates the gene expression of proteins involved in cholesterol transport in cell membrane (13). 7-Ketocholesterol, nonenzymatic oxidation product of cholesterol, has been shown to induce cell death through inactivation of the phosphatidylinositol 3-kinase/Akt signaling pathway (14), which is considered to be highly specific to lipid raft domains (15). 24S-OHC has been shown to possess potent neurotoxicity (16); however, the molecular mechanisms of the induction of neurotoxicity, particularly in the form of cell death, are less clearly defined.…”

α-Tocopherols modify the membrane dipole potential leading to modulation of ligand binding by P-glycoprotein

“…Our observations may therefore apply to a variety of proteins and different cell types. ␣ -Tocopherol, through its localization in membrane microdomains ( 43 ), may infl uence the function of microdomain-associated proteins via the same mechanism we propose for ␣ -tocopherol succinate. Indeed the ubiquity of this mechanism may help to explain the diverse and sometimes apparently contradictory actions which have been ascribed to vitamin E.…”

“…We hypothesize that the mechanism by which ␣ -tocopherol succinate infl uences P-gp is via its effect to decrease the dipole potential of membrane microdomains with which this receptor associates. In support of this notion, 7-ketocholesterol, an oxidized form of cholesterol known to localize in cholesterol-rich microdomains ( 42,43 ) and demonstrated to decrease the dipole potential of the plasma membrane, was also shown to infl uence the interaction of saquinavir with P-gp. The apparent differences in the extent to which ␣ -tocopherol succinate and 7-ketocholesterol infl uence both the dipole potential and P-gp are suggested to be due to differences in their heterogeneous lateral distribution within membranes and, in particular, their extent of colocalization with P-gp in microdomains.…”

Present trends in vitamin E research

“…This view, however, is not universally accepted and an association of a-tocopherol with lipid rafts has been recently described [11]. This association was observed for a-tocopherol but not for c-tocopherol.…”