Identification of Dehydroxytrichostatin A as a Novel Up-Regulator of the ATP-Binding Cassette Transporter A1 ABCA1Report as inadecuate




Identification of Dehydroxytrichostatin A as a Novel Up-Regulator of the ATP-Binding Cassette Transporter A1 ABCA1 - Download this document for free, or read online. Document in PDF available to download.

Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China



These authors contributed equally to this work.





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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.

Keywords: dehydroxytrichostatin A; atherosclerosis; ABCA1; up-regulator; HDAC inhibitor dehydroxytrichostatin A; atherosclerosis; ABCA1; up-regulator; HDAC inhibitor





Author: Yang Xu †, Yanni Xu †, Yi Bao, Bin Hong * and Shuyi Si *

Source: http://mdpi.com/



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