Loading…
Regulation of liver X receptor target genes by 22-functionalized oxysterols. Synthesis, in silico and in vitro evaluations
[Display omitted] •New oxysterol based LXR-modulators have been synthesized.•Importance of the 22th position of the oxysterol scaffold has been investigated.•Compounds were evaluated in silico and in vitro for regulation of key LXR-target genes.•22-Ketocholesterol downregulates ABCA1 selectively.•A...
Saved in:
Published in: | Steroids 2017-02, Vol.118, p.119-127 |
---|---|
Main Authors: | , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
cited_by | cdi_FETCH-LOGICAL-c368t-7db32efc6393d4ab43cb46099ee575962eac85d17dddcb35ab3db3c9fac75b2b3 |
---|---|
cites | cdi_FETCH-LOGICAL-c368t-7db32efc6393d4ab43cb46099ee575962eac85d17dddcb35ab3db3c9fac75b2b3 |
container_end_page | 127 |
container_issue | |
container_start_page | 119 |
container_title | Steroids |
container_volume | 118 |
creator | Viktorsson, Elvar Örn Gabrielsen, Mari Kumarachandran, Nugalya Sylte, Ingebrigt Rongved, Pål Åstrand, Ove Alexander Høgmoen Kase, Eili Tranheim |
description | [Display omitted]
•New oxysterol based LXR-modulators have been synthesized.•Importance of the 22th position of the oxysterol scaffold has been investigated.•Compounds were evaluated in silico and in vitro for regulation of key LXR-target genes.•22-Ketocholesterol downregulates ABCA1 selectively.•A new oxysterol analog was found to reduce lipogenesis.
The endogenous oxysterol 22(R)-hydroxycholesterol (22RHC, 1) is an LXR agonist which upregulates genes of critical involvement in human cholesterol- and lipid metabolism. In contrast, its synthetic epimer 22(S)-hydroxycholesterol (22SHC, 8) has shown specific antagonistic effects in recent studies, avoiding unwanted side effects provided by potent LXR agonists. In terms of LXR modulation, the aim of this study was to compare 22SHC (8), 22RHC (1) and synthesized ligands with keto- and amide functionality in the 22nd position of the cholesterol scaffold. 22SHC (8) and 22RHC (1) performed as expected while 22-ketocholesterol (22KC, 10) revealed an attractive in vitro profile for further investigation in terms of anti-atherosclerotic properties as selective upregulation of the ATP-binding cassette transporter ABCA1 was observed. A new synthesized amide derivate, Fernholtz cyclohexylamide (13) was shown to reduce lipogenesis in a dose-responsive manner and abolish the effect of the potent LXR agonist T0901317 when administered simultaneously. |
doi_str_mv | 10.1016/j.steroids.2016.12.003 |
format | article |
fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1852785732</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0039128X16301829</els_id><sourcerecordid>1852785732</sourcerecordid><originalsourceid>FETCH-LOGICAL-c368t-7db32efc6393d4ab43cb46099ee575962eac85d17dddcb35ab3db3c9fac75b2b3</originalsourceid><addsrcrecordid>eNqFkEtvEzEURi0EoqHwFyovWTCDH5kZzw5U8ZIqIfGQurP8uBMcOePg64lIfz1O07JlZV3rfP6uDyFXnLWc8f7ttsUCOQWPrahzy0XLmHxCVlwNqulUPzwlq3ozNlyo2wvyAnHLGOvlKJ6TC6EY51zKFbn7BpslmhLSTNNEYzhAprc0g4N9SZkWkzdQ6AZmQGqPVIhmWmZ34k0Md-Bp-nO8XyViS78f5_ILMOAbGmaKIQaXqJn9aTqEkhOFg4nLfR2-JM8mExFePZyX5OfHDz-uPzc3Xz99uX5_0zjZq9IM3koBk6urS782di2dXfdsHAG6oRt7AcapzvPBe--s7IyVNeHGybihs8LKS_L6_O4-p98LYNG7gA5iNDOkBTVXnRhUN0hR0f6MupwQM0x6n8PO5KPmTJ-8661-9K5P3jUXulquwauHjsXuwP-LPYquwLszAPWnhwBZowswO_Chui7ap_C_jr8mf5sa</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1852785732</pqid></control><display><type>article</type><title>Regulation of liver X receptor target genes by 22-functionalized oxysterols. Synthesis, in silico and in vitro evaluations</title><source>ScienceDirect Freedom Collection</source><creator>Viktorsson, Elvar Örn ; Gabrielsen, Mari ; Kumarachandran, Nugalya ; Sylte, Ingebrigt ; Rongved, Pål ; Åstrand, Ove Alexander Høgmoen ; Kase, Eili Tranheim</creator><creatorcontrib>Viktorsson, Elvar Örn ; Gabrielsen, Mari ; Kumarachandran, Nugalya ; Sylte, Ingebrigt ; Rongved, Pål ; Åstrand, Ove Alexander Høgmoen ; Kase, Eili Tranheim</creatorcontrib><description>[Display omitted]
•New oxysterol based LXR-modulators have been synthesized.•Importance of the 22th position of the oxysterol scaffold has been investigated.•Compounds were evaluated in silico and in vitro for regulation of key LXR-target genes.•22-Ketocholesterol downregulates ABCA1 selectively.•A new oxysterol analog was found to reduce lipogenesis.
The endogenous oxysterol 22(R)-hydroxycholesterol (22RHC, 1) is an LXR agonist which upregulates genes of critical involvement in human cholesterol- and lipid metabolism. In contrast, its synthetic epimer 22(S)-hydroxycholesterol (22SHC, 8) has shown specific antagonistic effects in recent studies, avoiding unwanted side effects provided by potent LXR agonists. In terms of LXR modulation, the aim of this study was to compare 22SHC (8), 22RHC (1) and synthesized ligands with keto- and amide functionality in the 22nd position of the cholesterol scaffold. 22SHC (8) and 22RHC (1) performed as expected while 22-ketocholesterol (22KC, 10) revealed an attractive in vitro profile for further investigation in terms of anti-atherosclerotic properties as selective upregulation of the ATP-binding cassette transporter ABCA1 was observed. A new synthesized amide derivate, Fernholtz cyclohexylamide (13) was shown to reduce lipogenesis in a dose-responsive manner and abolish the effect of the potent LXR agonist T0901317 when administered simultaneously.</description><identifier>ISSN: 0039-128X</identifier><identifier>EISSN: 1878-5867</identifier><identifier>DOI: 10.1016/j.steroids.2016.12.003</identifier><identifier>PMID: 28011133</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Biological evaluation ; Cholesterol - analogs & derivatives ; Cholesterol - chemistry ; Cholesterol - metabolism ; Hep G2 Cells ; Humans ; Liver X receptors ; Liver X Receptors - metabolism ; Magnetic Resonance Spectroscopy ; Molecular modelling ; Molecular Structure ; Oxysterols ; Oxysterols - metabolism ; Real-Time Polymerase Chain Reaction ; Steroid synthesis ; Steroids - chemistry ; Steroids - metabolism</subject><ispartof>Steroids, 2017-02, Vol.118, p.119-127</ispartof><rights>2016 Elsevier Inc.</rights><rights>Copyright © 2016 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c368t-7db32efc6393d4ab43cb46099ee575962eac85d17dddcb35ab3db3c9fac75b2b3</citedby><cites>FETCH-LOGICAL-c368t-7db32efc6393d4ab43cb46099ee575962eac85d17dddcb35ab3db3c9fac75b2b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28011133$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Viktorsson, Elvar Örn</creatorcontrib><creatorcontrib>Gabrielsen, Mari</creatorcontrib><creatorcontrib>Kumarachandran, Nugalya</creatorcontrib><creatorcontrib>Sylte, Ingebrigt</creatorcontrib><creatorcontrib>Rongved, Pål</creatorcontrib><creatorcontrib>Åstrand, Ove Alexander Høgmoen</creatorcontrib><creatorcontrib>Kase, Eili Tranheim</creatorcontrib><title>Regulation of liver X receptor target genes by 22-functionalized oxysterols. Synthesis, in silico and in vitro evaluations</title><title>Steroids</title><addtitle>Steroids</addtitle><description>[Display omitted]
•New oxysterol based LXR-modulators have been synthesized.•Importance of the 22th position of the oxysterol scaffold has been investigated.•Compounds were evaluated in silico and in vitro for regulation of key LXR-target genes.•22-Ketocholesterol downregulates ABCA1 selectively.•A new oxysterol analog was found to reduce lipogenesis.
The endogenous oxysterol 22(R)-hydroxycholesterol (22RHC, 1) is an LXR agonist which upregulates genes of critical involvement in human cholesterol- and lipid metabolism. In contrast, its synthetic epimer 22(S)-hydroxycholesterol (22SHC, 8) has shown specific antagonistic effects in recent studies, avoiding unwanted side effects provided by potent LXR agonists. In terms of LXR modulation, the aim of this study was to compare 22SHC (8), 22RHC (1) and synthesized ligands with keto- and amide functionality in the 22nd position of the cholesterol scaffold. 22SHC (8) and 22RHC (1) performed as expected while 22-ketocholesterol (22KC, 10) revealed an attractive in vitro profile for further investigation in terms of anti-atherosclerotic properties as selective upregulation of the ATP-binding cassette transporter ABCA1 was observed. A new synthesized amide derivate, Fernholtz cyclohexylamide (13) was shown to reduce lipogenesis in a dose-responsive manner and abolish the effect of the potent LXR agonist T0901317 when administered simultaneously.</description><subject>Biological evaluation</subject><subject>Cholesterol - analogs & derivatives</subject><subject>Cholesterol - chemistry</subject><subject>Cholesterol - metabolism</subject><subject>Hep G2 Cells</subject><subject>Humans</subject><subject>Liver X receptors</subject><subject>Liver X Receptors - metabolism</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Molecular modelling</subject><subject>Molecular Structure</subject><subject>Oxysterols</subject><subject>Oxysterols - metabolism</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Steroid synthesis</subject><subject>Steroids - chemistry</subject><subject>Steroids - metabolism</subject><issn>0039-128X</issn><issn>1878-5867</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNqFkEtvEzEURi0EoqHwFyovWTCDH5kZzw5U8ZIqIfGQurP8uBMcOePg64lIfz1O07JlZV3rfP6uDyFXnLWc8f7ttsUCOQWPrahzy0XLmHxCVlwNqulUPzwlq3ozNlyo2wvyAnHLGOvlKJ6TC6EY51zKFbn7BpslmhLSTNNEYzhAprc0g4N9SZkWkzdQ6AZmQGqPVIhmWmZ34k0Md-Bp-nO8XyViS78f5_ILMOAbGmaKIQaXqJn9aTqEkhOFg4nLfR2-JM8mExFePZyX5OfHDz-uPzc3Xz99uX5_0zjZq9IM3koBk6urS782di2dXfdsHAG6oRt7AcapzvPBe--s7IyVNeHGybihs8LKS_L6_O4-p98LYNG7gA5iNDOkBTVXnRhUN0hR0f6MupwQM0x6n8PO5KPmTJ-8661-9K5P3jUXulquwauHjsXuwP-LPYquwLszAPWnhwBZowswO_Chui7ap_C_jr8mf5sa</recordid><startdate>20170201</startdate><enddate>20170201</enddate><creator>Viktorsson, Elvar Örn</creator><creator>Gabrielsen, Mari</creator><creator>Kumarachandran, Nugalya</creator><creator>Sylte, Ingebrigt</creator><creator>Rongved, Pål</creator><creator>Åstrand, Ove Alexander Høgmoen</creator><creator>Kase, Eili Tranheim</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20170201</creationdate><title>Regulation of liver X receptor target genes by 22-functionalized oxysterols. Synthesis, in silico and in vitro evaluations</title><author>Viktorsson, Elvar Örn ; Gabrielsen, Mari ; Kumarachandran, Nugalya ; Sylte, Ingebrigt ; Rongved, Pål ; Åstrand, Ove Alexander Høgmoen ; Kase, Eili Tranheim</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c368t-7db32efc6393d4ab43cb46099ee575962eac85d17dddcb35ab3db3c9fac75b2b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Biological evaluation</topic><topic>Cholesterol - analogs & derivatives</topic><topic>Cholesterol - chemistry</topic><topic>Cholesterol - metabolism</topic><topic>Hep G2 Cells</topic><topic>Humans</topic><topic>Liver X receptors</topic><topic>Liver X Receptors - metabolism</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Molecular modelling</topic><topic>Molecular Structure</topic><topic>Oxysterols</topic><topic>Oxysterols - metabolism</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Steroid synthesis</topic><topic>Steroids - chemistry</topic><topic>Steroids - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Viktorsson, Elvar Örn</creatorcontrib><creatorcontrib>Gabrielsen, Mari</creatorcontrib><creatorcontrib>Kumarachandran, Nugalya</creatorcontrib><creatorcontrib>Sylte, Ingebrigt</creatorcontrib><creatorcontrib>Rongved, Pål</creatorcontrib><creatorcontrib>Åstrand, Ove Alexander Høgmoen</creatorcontrib><creatorcontrib>Kase, Eili Tranheim</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Steroids</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Viktorsson, Elvar Örn</au><au>Gabrielsen, Mari</au><au>Kumarachandran, Nugalya</au><au>Sylte, Ingebrigt</au><au>Rongved, Pål</au><au>Åstrand, Ove Alexander Høgmoen</au><au>Kase, Eili Tranheim</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Regulation of liver X receptor target genes by 22-functionalized oxysterols. Synthesis, in silico and in vitro evaluations</atitle><jtitle>Steroids</jtitle><addtitle>Steroids</addtitle><date>2017-02-01</date><risdate>2017</risdate><volume>118</volume><spage>119</spage><epage>127</epage><pages>119-127</pages><issn>0039-128X</issn><eissn>1878-5867</eissn><abstract>[Display omitted]
•New oxysterol based LXR-modulators have been synthesized.•Importance of the 22th position of the oxysterol scaffold has been investigated.•Compounds were evaluated in silico and in vitro for regulation of key LXR-target genes.•22-Ketocholesterol downregulates ABCA1 selectively.•A new oxysterol analog was found to reduce lipogenesis.
The endogenous oxysterol 22(R)-hydroxycholesterol (22RHC, 1) is an LXR agonist which upregulates genes of critical involvement in human cholesterol- and lipid metabolism. In contrast, its synthetic epimer 22(S)-hydroxycholesterol (22SHC, 8) has shown specific antagonistic effects in recent studies, avoiding unwanted side effects provided by potent LXR agonists. In terms of LXR modulation, the aim of this study was to compare 22SHC (8), 22RHC (1) and synthesized ligands with keto- and amide functionality in the 22nd position of the cholesterol scaffold. 22SHC (8) and 22RHC (1) performed as expected while 22-ketocholesterol (22KC, 10) revealed an attractive in vitro profile for further investigation in terms of anti-atherosclerotic properties as selective upregulation of the ATP-binding cassette transporter ABCA1 was observed. A new synthesized amide derivate, Fernholtz cyclohexylamide (13) was shown to reduce lipogenesis in a dose-responsive manner and abolish the effect of the potent LXR agonist T0901317 when administered simultaneously.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>28011133</pmid><doi>10.1016/j.steroids.2016.12.003</doi><tpages>9</tpages></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0039-128X |
ispartof | Steroids, 2017-02, Vol.118, p.119-127 |
issn | 0039-128X 1878-5867 |
language | eng |
recordid | cdi_proquest_miscellaneous_1852785732 |
source | ScienceDirect Freedom Collection |
subjects | Biological evaluation Cholesterol - analogs & derivatives Cholesterol - chemistry Cholesterol - metabolism Hep G2 Cells Humans Liver X receptors Liver X Receptors - metabolism Magnetic Resonance Spectroscopy Molecular modelling Molecular Structure Oxysterols Oxysterols - metabolism Real-Time Polymerase Chain Reaction Steroid synthesis Steroids - chemistry Steroids - metabolism |
title | Regulation of liver X receptor target genes by 22-functionalized oxysterols. Synthesis, in silico and in vitro evaluations |
url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T19%3A49%3A40IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Regulation%20of%20liver%20X%20receptor%20target%20genes%20by%2022-functionalized%20oxysterols.%20Synthesis,%20in%20silico%20and%20in%20vitro%20evaluations&rft.jtitle=Steroids&rft.au=Viktorsson,%20Elvar%20%C3%96rn&rft.date=2017-02-01&rft.volume=118&rft.spage=119&rft.epage=127&rft.pages=119-127&rft.issn=0039-128X&rft.eissn=1878-5867&rft_id=info:doi/10.1016/j.steroids.2016.12.003&rft_dat=%3Cproquest_cross%3E1852785732%3C/proquest_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c368t-7db32efc6393d4ab43cb46099ee575962eac85d17dddcb35ab3db3c9fac75b2b3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1852785732&rft_id=info:pmid/28011133&rfr_iscdi=true |