α-Tocopherol rescues lipid-induced impairment of autophagy via mTOR/ULK1 signaling in macrophages.
TL;DR
In vitro findings suggest that α-TOC reduces lipid accumulation and inhibits foam cell formation in macrophages by enhancing autophagic activity in association with reduced mTOR phosphorylation and increased ULK1 Ser555 phosphorylation.
Abstract
Atherosclerosis is a chronic vascular disease characterized by the accumulation of lipid-filled foam cells in the arterial wall. Macrophage-derived foam cells play a key role in promoting plaque formation. α-Tocopherol (α-TOC), a common dietary antioxidant, is thought to have protective effects against atherosclerosis, but its specific mechanisms remain unclear. In this study, an in vitro foam cell model was established using oxidized low-density lipoprotein-induced macrophages to investigate the effects of α-TOC on foam cell formation and related mechanisms. Network pharmacology predicted that α-TOC may act through autophagy-related pathways, particularly the mTOR-mediated autophagy pathway. We demonstrated that α-TOC enhanced autophagic function in macrophages, as evidenced by increased expression of Beclin1, LC3-II, ATG5, and ATG12, along with reduced p62/SQSTM1 levels. Rapamycin reproduced, and 3-methyladenine opposed, the direction of the autophagic and mTOR/ULK1 changes observed with α-TOC, consistent with involvement of this pathway. These in vitro findings suggest that α-TOC reduces lipid accumulation and inhibits foam cell formation in macrophages by enhancing autophagic activity in association with reduced mTOR phosphorylation and increased ULK1 Ser555 phosphorylation. This study provides mechanistic insights into the potential anti-atherosclerotic effects of α-TOC at the cellular level, offering a theoretical basis for its further investigation as a therapeutic candidate for atherosclerosis.