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Ligand-Regulated Heterodimerization of Peroxisome Proliferator-Activated Receptor α with Liver X Receptor α

[Image: see text] Peroxisome proliferator-activated receptor α (PPARα) and liver X receptor α (LXRα) are members of the nuclear receptor superfamily that function to regulate lipid metabolism. Complex interactions between the LXRα and PPARα pathways exist, including competition for the same heterodi...

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Autores principales: Balanarasimha, Madhumitha, Davis, Andrea M., Soman, Frances L., Rider, S. Dean, Hostetler, Heather A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007980/
https://www.ncbi.nlm.nih.gov/pubmed/24713062
http://dx.doi.org/10.1021/bi401679y
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author Balanarasimha, Madhumitha
Davis, Andrea M.
Soman, Frances L.
Rider, S. Dean
Hostetler, Heather A.
author_facet Balanarasimha, Madhumitha
Davis, Andrea M.
Soman, Frances L.
Rider, S. Dean
Hostetler, Heather A.
author_sort Balanarasimha, Madhumitha
collection PubMed
description [Image: see text] Peroxisome proliferator-activated receptor α (PPARα) and liver X receptor α (LXRα) are members of the nuclear receptor superfamily that function to regulate lipid metabolism. Complex interactions between the LXRα and PPARα pathways exist, including competition for the same heterodimeric partner, retinoid X receptor α (RXRα). Although data have suggested that PPARα and LXRα may interact directly, the role of endogenous ligands in such interactions has not been investigated. Using in vitro protein–protein binding assays, circular dichroism, and co-immunoprecipitation of endogenous proteins, we established that full-length human PPARα and LXRα interact with high affinity, resulting in altered protein conformations. We demonstrated for the first time that the affinity of this interaction and the resulting conformational changes could be altered by endogenous PPARα ligands, namely long chain fatty acids (LCFA) or their coenzyme A thioesters. This heterodimer pair was capable of binding to PPARα and LXRα response elements (PPRE and LXRE, respectively), albeit with an affinity lower than that of the respective heterodimers formed with RXRα. LCFA had little effect on binding to the PPRE but suppressed binding to the LXRE. Ectopic expression of PPARα and LXRα in mammalian cells yielded an increased level of PPRE transactivation compared to overexpression of PPARα alone and was largely unaffected by LCFA. Overexpression of both receptors also resulted in transactivation from an LXRE, with decreased levels compared to that of LXRα overexpression alone, and LCFA suppressed transactivation from the LXRE. These data are consistent with the hypothesis that ligand binding regulates heterodimer choice and downstream gene regulation by these nuclear receptors.
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spelling pubmed-40079802015-04-08 Ligand-Regulated Heterodimerization of Peroxisome Proliferator-Activated Receptor α with Liver X Receptor α Balanarasimha, Madhumitha Davis, Andrea M. Soman, Frances L. Rider, S. Dean Hostetler, Heather A. Biochemistry [Image: see text] Peroxisome proliferator-activated receptor α (PPARα) and liver X receptor α (LXRα) are members of the nuclear receptor superfamily that function to regulate lipid metabolism. Complex interactions between the LXRα and PPARα pathways exist, including competition for the same heterodimeric partner, retinoid X receptor α (RXRα). Although data have suggested that PPARα and LXRα may interact directly, the role of endogenous ligands in such interactions has not been investigated. Using in vitro protein–protein binding assays, circular dichroism, and co-immunoprecipitation of endogenous proteins, we established that full-length human PPARα and LXRα interact with high affinity, resulting in altered protein conformations. We demonstrated for the first time that the affinity of this interaction and the resulting conformational changes could be altered by endogenous PPARα ligands, namely long chain fatty acids (LCFA) or their coenzyme A thioesters. This heterodimer pair was capable of binding to PPARα and LXRα response elements (PPRE and LXRE, respectively), albeit with an affinity lower than that of the respective heterodimers formed with RXRα. LCFA had little effect on binding to the PPRE but suppressed binding to the LXRE. Ectopic expression of PPARα and LXRα in mammalian cells yielded an increased level of PPRE transactivation compared to overexpression of PPARα alone and was largely unaffected by LCFA. Overexpression of both receptors also resulted in transactivation from an LXRE, with decreased levels compared to that of LXRα overexpression alone, and LCFA suppressed transactivation from the LXRE. These data are consistent with the hypothesis that ligand binding regulates heterodimer choice and downstream gene regulation by these nuclear receptors. American Chemical Society 2014-04-08 2014-04-29 /pmc/articles/PMC4007980/ /pubmed/24713062 http://dx.doi.org/10.1021/bi401679y Text en Copyright © 2014 American Chemical Society
spellingShingle Balanarasimha, Madhumitha
Davis, Andrea M.
Soman, Frances L.
Rider, S. Dean
Hostetler, Heather A.
Ligand-Regulated Heterodimerization of Peroxisome Proliferator-Activated Receptor α with Liver X Receptor α
title Ligand-Regulated Heterodimerization of Peroxisome Proliferator-Activated Receptor α with Liver X Receptor α
title_full Ligand-Regulated Heterodimerization of Peroxisome Proliferator-Activated Receptor α with Liver X Receptor α
title_fullStr Ligand-Regulated Heterodimerization of Peroxisome Proliferator-Activated Receptor α with Liver X Receptor α
title_full_unstemmed Ligand-Regulated Heterodimerization of Peroxisome Proliferator-Activated Receptor α with Liver X Receptor α
title_short Ligand-Regulated Heterodimerization of Peroxisome Proliferator-Activated Receptor α with Liver X Receptor α
title_sort ligand-regulated heterodimerization of peroxisome proliferator-activated receptor α with liver x receptor α
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007980/
https://www.ncbi.nlm.nih.gov/pubmed/24713062
http://dx.doi.org/10.1021/bi401679y
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