Cargando…

Identification of Dehydroxytrichostatin A as a Novel Up-Regulator of the ATP-Binding Cassette Transporter A1 (ABCA1)

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 screenin...

Descripción completa

Detalles Bibliográficos
Autores principales: Xu, Yang, Xu, Yanni, Bao, Yi, Hong, Bin, Si, Shuyi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264683/
https://www.ncbi.nlm.nih.gov/pubmed/21869747
http://dx.doi.org/10.3390/molecules16097183
_version_ 1783375548286763008
author Xu, Yang
Xu, Yanni
Bao, Yi
Hong, Bin
Si, Shuyi
author_facet Xu, Yang
Xu, Yanni
Bao, Yi
Hong, Bin
Si, Shuyi
author_sort Xu, Yang
collection PubMed
description 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 EC(50) 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 IC(50) 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.
format Online
Article
Text
id pubmed-6264683
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-62646832018-12-10 Identification of Dehydroxytrichostatin A as a Novel Up-Regulator of the ATP-Binding Cassette Transporter A1 (ABCA1) Xu, Yang Xu, Yanni Bao, Yi Hong, Bin Si, Shuyi Molecules Article 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 EC(50) 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 IC(50) 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. MDPI 2011-08-25 /pmc/articles/PMC6264683/ /pubmed/21869747 http://dx.doi.org/10.3390/molecules16097183 Text en © 2011 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
Xu, Yang
Xu, Yanni
Bao, Yi
Hong, Bin
Si, Shuyi
Identification of Dehydroxytrichostatin A as a Novel Up-Regulator of the ATP-Binding Cassette Transporter A1 (ABCA1)
title Identification of Dehydroxytrichostatin A as a Novel Up-Regulator of the ATP-Binding Cassette Transporter A1 (ABCA1)
title_full Identification of Dehydroxytrichostatin A as a Novel Up-Regulator of the ATP-Binding Cassette Transporter A1 (ABCA1)
title_fullStr Identification of Dehydroxytrichostatin A as a Novel Up-Regulator of the ATP-Binding Cassette Transporter A1 (ABCA1)
title_full_unstemmed Identification of Dehydroxytrichostatin A as a Novel Up-Regulator of the ATP-Binding Cassette Transporter A1 (ABCA1)
title_short Identification of Dehydroxytrichostatin A as a Novel Up-Regulator of the ATP-Binding Cassette Transporter A1 (ABCA1)
title_sort identification of dehydroxytrichostatin a as a novel up-regulator of the atp-binding cassette transporter a1 (abca1)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264683/
https://www.ncbi.nlm.nih.gov/pubmed/21869747
http://dx.doi.org/10.3390/molecules16097183
work_keys_str_mv AT xuyang identificationofdehydroxytrichostatinaasanovelupregulatoroftheatpbindingcassettetransportera1abca1
AT xuyanni identificationofdehydroxytrichostatinaasanovelupregulatoroftheatpbindingcassettetransportera1abca1
AT baoyi identificationofdehydroxytrichostatinaasanovelupregulatoroftheatpbindingcassettetransportera1abca1
AT hongbin identificationofdehydroxytrichostatinaasanovelupregulatoroftheatpbindingcassettetransportera1abca1
AT sishuyi identificationofdehydroxytrichostatinaasanovelupregulatoroftheatpbindingcassettetransportera1abca1