Abstract
The ATP-binding cassette transporter A1 (ABCA1) mediates the cellular efflux of excess cholesterol and phospholipids to lipid-poor apolipoprotein A-I (apoA-I). ABCA1 plays an important role in high-density lipoprotein (HDL) biogenesis and reverse cholesterol transport. By using a cell-based screening model for the ABCA1 up-regulator and column chromatography, an active compound, 9179B, was isolated. Through analysis of its NMR data, 9179B was identified as dehydroxytrichostatin A. We found that 9179B increased the transcription of ABCA1 in a cell-based reporter assay, with an EC50 value of 2.65 μM. 9179B up-regulated ABCA1 expression at both mRNA and protein levels in HepG2 and RAW264.7 cells. It also up-regulated the expression of scavenger receptor class B type I (SR-BI) as well as the uptake of DiI-HDL in RAW264.7 cells. This compound stimulated ApoA-I-mediated cellular cholesterol efflux from RAW 264.7 cells. We further found that 9179B was a potent histone deacetylase (HDAC) inhibitor with an IC50 value of 0.08 μM. Reporter gene assays showed that the regulation of ABCA1 transcription by 9179B was mainly mediated by the −171/−75 bp promoter region. Together, our results indicate that 9179B is an ABCA1 up-regulator and dehydroxytrichostatin A may be a novel anti-atherogenic compound.
Highlights
Cardiovascular disease (CVD) is a major threat to human health and atherosclerosis (AS) is the principal pathogenesis of CVD
Our results indicate that 9179B is an ATP-binding cassette transporter A1 (ABCA1) up-regulator and dehydroxytrichostatin A may be a novel anti-atherogenic compound
In this paper we report for the first time the identification and characterization of dehydroxytrichostatin A (9179B) as a novel up-regulator of ABCA1
Summary
Cardiovascular disease (CVD) is a major threat to human health and atherosclerosis (AS) is the principal pathogenesis of CVD. HDL-C levels are associated with low morbidity and mortality rates of CVD [4]. Considerable evidence shows that therapeutically elevating HDL-C levels may be beneficial for CVD. The ATP-binding cassette transporter A1 (ABCA1) is a membrane transporter, which is highly expressed in placenta, brain, adrenal glands and liver [5]. It mediates the rate-controlling step in HDL particle formation as well as the efflux of cellular phospholipids and cholesterol to lipid-free apolipoprotein A-I (apoA-I), which may account for the atheroprotective effect of HDL [6,7]. Treatment of HepG2 cells with 9179B and the cis-elements in ABCA1 promoter up-regulates ABCA1 expression
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