Modulation of CD36‐mediated lipid accumulation and senescence by vitamin E analogs in monocytes and macrophages

Abstract

The CD36/FAT scavenger receptor/fatty acids transporter regulates cellular lipid accumulation important for inflammation, atherosclerosis, lipotoxicity, and initiation of cellular senescence. Here we compared the regulatory effects of the vitamin E analogs alpha‐tocopherol (αT), alpha‐tocopheryl phosphate (αTP), and αTP/βCD (a nanocarrier complex between αTP and β‐cyclodextrin [βCD]) and investigated their regulatory effects on lipid accumulation, phagocytosis, and senescence in THP‐1 monocytes and macrophages. Both, αTP and αTP/βCD inhibited CD36 surface exposition stronger than αT leading to more pronounced CD36‐mediated events such as inhibition of DiI‐labeled oxLDL uptake, phagocytosis of fluorescent Staphylococcus aureus bioparticles, and cell proliferation. When compared to βCD, the complex of αTP/βCD extracted cholesterol from cellular membranes with higher efficiency and was associated with the delivery of αTP to the cells. Interestingly, both, αTP and more so αTP/βCD inhibited lysosomal senescence‐associated beta‐galactosidase (SA‐β‐gal) activity and increased lysosomal pH, suggesting CD36‐mediated uptake into the endo‐lysosomal phagocytic compartment. Accordingly, the observed pH increase was more pronounced with αTP/βCD in macrophages whereas no significant increase occurred with αT, alpha‐tocopheryl acetate (αTA) or βCD. In contrast to αT and αTA, the αTP molecule is di‐anionic at neutral pH, but upon moving into the acidic endo‐lysosomal compartment becomes protonated and thus is acting as a base. Moreover, it is expected to be retained in lysosomes since it still carries one negative charge, similar to lysosomotropic drugs. Thus, treatment with αTP or αTP/βCD and/or inhibition of conversion of αTP to αT as it occurs in aged cells may counteract CD36‐mediated overlapping inflammatory, senescent, and atherosclerotic events.