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

Abstract

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

Role of ABCA1 in Cardiovascular Disease

“…In vascular smooth muscle cells, the inhibition of myocardin regulates ABCA1 to prevent atherosclerosis [ 189 ]. Recently, E17241 (4-(1,3-dithiolan-2-yl)-N-(3-hydroxypyridin-2-yl) benzamide) was identified as a novel ABCA1 upregulator and reduced atherosclerotic lesion areas in vivo in animal models [ 190 ]. An in vitro study showed that mangiferin, an agonist of NFE2 like bZIP transcription factor 2, obviously reduced TC, TG, and LDL-c levels by augmenting the expression of ABCA1 [ 164 ].…”

Apolipoprotein A1-Related Proteins and Reverse Cholesterol Transport in Antiatherosclerosis Therapy: Recent Progress and Future Perspectives

“…We need to explore the influence of single miRNA-target interaction further and develop new methods to regulate miRNA biology. In addition to noncoding RNA molecules, there are also some compounds such as E17241 and N-benzothiazolyl-2-benzenesulfonamide that promote cholesterol efflux by enhancing ABCA1 mRNA and protein expression in cells and have been identified as novel ABCA1 expression upregulators [38,39]. Some substances, including leonurine, E3317, mangiferin, Shen-Hong-Tong-Luo, and celastrol, prevent AS via the oxidative stress pathway or participate in the inflammatory response to enhance ABCA1 function by upregulating the expression of ABCA1 via the peroxisome proliferator-activated receptor gamma (PPAR-γ)/liver X receptor alpha (LXR-α)/ABCA1 pathway; this promotes cholesterol efflux and reduces lipid accumulation, thus preventing AS [40][41][42][43][44].…”

“…We need to explore the influence of single miRNA-target interaction further and develop new methods to regulate miRNA biology. In addition to noncoding RNA molecules, there are also some compounds such as E17241 and N -benzothiazolyl-2-benzenesulfonamide that promote cholesterol efflux by enhancing ABCA1 mRNA and protein expression in cells and have been identified as novel ABCA1 expression upregulators [ 38 , 39 ].…”

A New Small Molecule Increases Cholesterol Efflux

“…In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Xu et al 18 identify the small molecule E17241 in an ABCA1 promoter luciferase reporter assay high-throughput screen in HepG2 cells. E17241 dose-dependently upregulates Abca1 mRNA expression in macrophages and hepatocytes and increases macrophage cholesterol efflux to apolipoprotein A-I in vitro and macrophage reverse cholesterol transport in vivo.…”

“…At 2 different doses, daily gavage of E17241 showed atheroprotective effects in mice deficient in apolipoprotein E ( Apoe −/− mice) fed a Western-type diet, accompanied by increases in Abca1 protein expression in macrophages of atherosclerotic plaques and in hepatocytes. 18 Plasma levels of HDL-cholesterol were not affected, presumably because hepatic levels of the scavenger receptor BI (SR-BI) were also increased by E17241. E17241 decreased plasma ALT (alanine aminotransferase) and AST (aspartate transaminase) levels, suggesting no hepatic toxicity.…”