Fatty acid binding profile of the liver X receptor α
Liver X receptor (LXR)α is a nuclear receptor that responds to oxysterols and cholesterol overload by stimulating cholesterol efflux, transport, conversion to bile acids, and excretion. LXRα binds to and is regulated by synthetic (T-0901317, GW3695) and endogenous (oxysterols) ligands. LXRα activity...
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doaj-eebd1de709974659b8ad3b1d7c9ca6652021-04-29T04:35:01ZengElsevierJournal of Lipid Research0022-22752017-02-01582393402Fatty acid binding profile of the liver X receptor αShimpi Bedi0Genesis Victoria Hines1Valery V. Lozada-Fernandez2Camila de Jesus Piva3Alagammai Kaliappan4S.Dean Rider, Jr.5Heather A. Hostetler6Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435To whom correspondence should be addressed.; Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435Liver X receptor (LXR)α is a nuclear receptor that responds to oxysterols and cholesterol overload by stimulating cholesterol efflux, transport, conversion to bile acids, and excretion. LXRα binds to and is regulated by synthetic (T-0901317, GW3695) and endogenous (oxysterols) ligands. LXRα activity is also modulated by FAs, but the ligand binding specificity of FA and acyl-CoA derivatives for LXRα remains unknown. We investigated whether LXRα binds FA or FA acyl-CoA with affinities that mimic in vivo concentrations, examined the effect of FA chain length and the degree of unsaturation on binding, and investigated whether FAs regulate LXRα activation. Saturated medium-chain FA (MCFA) displayed binding affinities in the low nanomolar concentration range, while long-chain fatty acyl-CoA did not bind or bound weakly to LXRα. Circular dichroic spectra and computational docking experiments confirmed that MCFA bound to the LXRα ligand binding pocket similar to the known synthetic agonist of LXRα (T0901317), but with limited change to the conformation of the receptor. Transactivation assays showed that MCFA activated LXRα, whereas long-chain FA caused no effect. Our results suggest that LXRα functions as a receptor for saturated FA or acyl-CoA of C10 and C12 in length.http://www.sciencedirect.com/science/article/pii/S0022227520314206human liver X receptor αperoxisome proliferator-activated receptortranscription factorendogenous ligandmedium-chain fatty acidlong-chain fatty acid |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shimpi Bedi Genesis Victoria Hines Valery V. Lozada-Fernandez Camila de Jesus Piva Alagammai Kaliappan S.Dean Rider, Jr. Heather A. Hostetler |
spellingShingle |
Shimpi Bedi Genesis Victoria Hines Valery V. Lozada-Fernandez Camila de Jesus Piva Alagammai Kaliappan S.Dean Rider, Jr. Heather A. Hostetler Fatty acid binding profile of the liver X receptor α Journal of Lipid Research human liver X receptor α peroxisome proliferator-activated receptor transcription factor endogenous ligand medium-chain fatty acid long-chain fatty acid |
author_facet |
Shimpi Bedi Genesis Victoria Hines Valery V. Lozada-Fernandez Camila de Jesus Piva Alagammai Kaliappan S.Dean Rider, Jr. Heather A. Hostetler |
author_sort |
Shimpi Bedi |
title |
Fatty acid binding profile of the liver X receptor α |
title_short |
Fatty acid binding profile of the liver X receptor α |
title_full |
Fatty acid binding profile of the liver X receptor α |
title_fullStr |
Fatty acid binding profile of the liver X receptor α |
title_full_unstemmed |
Fatty acid binding profile of the liver X receptor α |
title_sort |
fatty acid binding profile of the liver x receptor α |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
2017-02-01 |
description |
Liver X receptor (LXR)α is a nuclear receptor that responds to oxysterols and cholesterol overload by stimulating cholesterol efflux, transport, conversion to bile acids, and excretion. LXRα binds to and is regulated by synthetic (T-0901317, GW3695) and endogenous (oxysterols) ligands. LXRα activity is also modulated by FAs, but the ligand binding specificity of FA and acyl-CoA derivatives for LXRα remains unknown. We investigated whether LXRα binds FA or FA acyl-CoA with affinities that mimic in vivo concentrations, examined the effect of FA chain length and the degree of unsaturation on binding, and investigated whether FAs regulate LXRα activation. Saturated medium-chain FA (MCFA) displayed binding affinities in the low nanomolar concentration range, while long-chain fatty acyl-CoA did not bind or bound weakly to LXRα. Circular dichroic spectra and computational docking experiments confirmed that MCFA bound to the LXRα ligand binding pocket similar to the known synthetic agonist of LXRα (T0901317), but with limited change to the conformation of the receptor. Transactivation assays showed that MCFA activated LXRα, whereas long-chain FA caused no effect. Our results suggest that LXRα functions as a receptor for saturated FA or acyl-CoA of C10 and C12 in length. |
topic |
human liver X receptor α peroxisome proliferator-activated receptor transcription factor endogenous ligand medium-chain fatty acid long-chain fatty acid |
url |
http://www.sciencedirect.com/science/article/pii/S0022227520314206 |
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