Methyl tertiary-butyl ether inhibits THP-1 macrophage cholesterol efflux in vitro and accelerates atherosclerosis in ApoE-deficient mice in vivo.

The biosafety of methyl tertiary-butyl ether (MTBE), mainly used as a gasoline additive, has long been a contentious topic. In addition to its routine toxicities, MTBE has been demonstrated to disrupt glucose and lipid metabolism and contribute to the development of type 2 diabetes as well as obesity. As one of the morbidities related to dyslipidemia, atherosclerosis is worthy of being investigated under MTBE exposure. Since foam cells derived from macrophages play pivotal roles during atherosclerosis development, we studied the effects of MTBE on macrophages in vitro and assessed the effect of MTBE on atherosclerosis plaque formation with the ApoE-/- mouse model in vivo for the first time. Our results demonstrated that exposure to MTBE at environmentally relevant concentrations decreased the expression of ABCA1 and ABCG1, which are responsible for macrophage cholesterol efflux, at both mRNA and protein levels in THP-1 macrophages. Consequently, treatment with MTBE inhibited the transport of cholesterol from macrophages to High-density lipoprotein. ApoE-/- mice exposed to MTBE at environmentally relevant concentrations (100, 1000 μg/kg) displayed significant increases in lesion area in the aorta and aortic root compared to vehicle-treated ones. Further analysis indicated that MTBE exposure enhanced the macrophage-specific marker Mac-2 contents within plaques in the aortic root, implying that MTBE could promote macrophage-derived foam cell formation and thus accelerate atherosclerosis plaque formation. We for the first time demonstrated the pro-atherogenic effect of MTBE via eliciting disruption of macrophage cholesterol efflux and accelerating foam cell formation and atherosclerosis plaque development.