Divergence between human and murine peroxisome proliferator-activated receptor alpha ligand specificities
Peroxisome proliferator-activated receptor α (PPARα) belongs to the family of ligand-dependent nuclear transcription factors that regulate energy metabolism. Although there exists remarkable overlap in the activities of PPARα across species, studies utilizing exogenous PPARα ligands suggest species...
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| Format: | Article |
| Language: | English |
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Elsevier
2013-09-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520351269 |
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| author | Dhawal P. Oswal Madhumitha Balanarasimha Jeannette K. Loyer Shimpi Bedi Frances L. Soman S. Dean Rider, Jr. Heather A. Hostetler |
| author_facet | Dhawal P. Oswal Madhumitha Balanarasimha Jeannette K. Loyer Shimpi Bedi Frances L. Soman S. Dean Rider, Jr. Heather A. Hostetler |
| author_sort | Dhawal P. Oswal |
| collection | DOAJ |
| description | Peroxisome proliferator-activated receptor α (PPARα) belongs to the family of ligand-dependent nuclear transcription factors that regulate energy metabolism. Although there exists remarkable overlap in the activities of PPARα across species, studies utilizing exogenous PPARα ligands suggest species differences in binding, activation, and physiological effects. While unsaturated long-chain fatty acids (LCFA) and their thioesters (long-chain fatty acyl-CoA; LCFA-CoA) function as ligands for recombinant mouse PPARα (mPPARα), no such studies have been conducted with full-length human PPARα (hPPARα). The objective of the current study was to determine whether LCFA and LCFA-CoA constitute high-affinity endogenous ligands for hPPARα or whether there exist species differences for ligand specificity and affinity. Both hPPARα and mPPARα bound with high affinity to LCFA-CoA; however, differences were noted in LCFA affinities. A fluorescent LCFA analog was bound strongly only by mPPARα, and naturally occurring saturated LCFA was bound more strongly by hPPARα than mPPARα. Similarly, unsaturated LCFA induced transactivation of both hPPARα and mPPARα, whereas saturated LCFA induced transactivation only in hPPARα-expressing cells. These data identified LCFA and LCFA-CoA as endogenous ligands of hPPARα, demonstrated species differences in binding specificity and activity, and may help delineate the role of PPARα as a nutrient sensor in metabolic regulation. |
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| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-18T01:40:18Z |
| publishDate | 2013-09-01 |
| publisher | Elsevier |
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| series | Journal of Lipid Research |
| spelling | doaj.art-9fbf65c7011a447195969b6bbf34e7152022-12-21T21:25:22ZengElsevierJournal of Lipid Research0022-22752013-09-0154923542365Divergence between human and murine peroxisome proliferator-activated receptor alpha ligand specificitiesDhawal P. Oswal0Madhumitha Balanarasimha1Jeannette K. Loyer2Shimpi Bedi3Frances L. Soman4S. Dean Rider, Jr.5Heather A. Hostetler6Department of Biochemistry & Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435Department of Biochemistry & Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435Department of Biochemistry & Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435Department of Biochemistry & Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435Department of Biochemistry & Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435Department of Biochemistry & Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435To whom correspondence should be addressed; Department of Biochemistry & Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435Peroxisome proliferator-activated receptor α (PPARα) belongs to the family of ligand-dependent nuclear transcription factors that regulate energy metabolism. Although there exists remarkable overlap in the activities of PPARα across species, studies utilizing exogenous PPARα ligands suggest species differences in binding, activation, and physiological effects. While unsaturated long-chain fatty acids (LCFA) and their thioesters (long-chain fatty acyl-CoA; LCFA-CoA) function as ligands for recombinant mouse PPARα (mPPARα), no such studies have been conducted with full-length human PPARα (hPPARα). The objective of the current study was to determine whether LCFA and LCFA-CoA constitute high-affinity endogenous ligands for hPPARα or whether there exist species differences for ligand specificity and affinity. Both hPPARα and mPPARα bound with high affinity to LCFA-CoA; however, differences were noted in LCFA affinities. A fluorescent LCFA analog was bound strongly only by mPPARα, and naturally occurring saturated LCFA was bound more strongly by hPPARα than mPPARα. Similarly, unsaturated LCFA induced transactivation of both hPPARα and mPPARα, whereas saturated LCFA induced transactivation only in hPPARα-expressing cells. These data identified LCFA and LCFA-CoA as endogenous ligands of hPPARα, demonstrated species differences in binding specificity and activity, and may help delineate the role of PPARα as a nutrient sensor in metabolic regulation.http://www.sciencedirect.com/science/article/pii/S0022227520351269PPARtranscription factorendogenous ligandspecies differencesfatty acidlong chain fatty acyl-CoA |
| spellingShingle | Dhawal P. Oswal Madhumitha Balanarasimha Jeannette K. Loyer Shimpi Bedi Frances L. Soman S. Dean Rider, Jr. Heather A. Hostetler Divergence between human and murine peroxisome proliferator-activated receptor alpha ligand specificities Journal of Lipid Research PPAR transcription factor endogenous ligand species differences fatty acid long chain fatty acyl-CoA |
| title | Divergence between human and murine peroxisome proliferator-activated receptor alpha ligand specificities |
| title_full | Divergence between human and murine peroxisome proliferator-activated receptor alpha ligand specificities |
| title_fullStr | Divergence between human and murine peroxisome proliferator-activated receptor alpha ligand specificities |
| title_full_unstemmed | Divergence between human and murine peroxisome proliferator-activated receptor alpha ligand specificities |
| title_short | Divergence between human and murine peroxisome proliferator-activated receptor alpha ligand specificities |
| title_sort | divergence between human and murine peroxisome proliferator activated receptor alpha ligand specificities |
| topic | PPAR transcription factor endogenous ligand species differences fatty acid long chain fatty acyl-CoA |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520351269 |
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