E17241 as a Novel ABCA1 (ATP-Binding Cassette Transporter A1) Upregulator Ameliorates Atherosclerosis in Mice

Objective: Reverse cholesterol transport, removing excess from peripheral tissues, is an important therapeutic target for atherosclerosis treatment. In this study, we propose a new small molecule, E17241, that may be used to treat by promoting reverse transport via ABCA1 (ATP-binding cassette transporter A1) upregulation. Approach and Results: E17241 (4-(1,3-dithiolan-2-yl)-N-(3-hydroxypyridin-2-yl)benzamide) was first identified as upregulator using cell-based reporter assay. significantly increases the mRNA protein expression levels of in both hepatic cells macrophages. It promotes efflux apo AI macrophage cells, effect depends on ABCA1. also decreases total content Ox-LDL (oxidized low-density lipoprotein) loading cells. treatment 3 H-labeled feces male C57BL/6J mice intraperitoneally injected with H-cholesterol-labeled J774 indicating it could promote vivo transport. Compared western diet group (western diet–fed ApoE −/− mice), diet+E17241 treatment) shows decreased plasma cholesterol, liver triglyceride levels, increased fecal content. Importantly, reduces atherosclerotic lesion areas en face aorta aortic sinus while increasing Human proteome microarray, coimmunoprecipitation, other assays demonstrate PKCζ (protein kinase C zeta) binding molecule macrophages PKCζ-NR (nuclear receptor) pathway. Conclusions: developed lead or drug candidate upregulating