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Coordinate Regulation of Lipid Metabolism by Novel Nuclear Receptor Partnerships

Mammalian nuclear receptors broadly influence metabolic fitness and serve as popular targets for developing drugs to treat cardiovascular disease, obesity, and diabetes. However, the molecular mechanisms and regulatory pathways that govern lipid metabolism remain poorly understood. We previously fou...

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Autores principales: Pathare, Pranali P., Lin, Alex, Bornfeldt, Karin E., Taubert, Stefan, Van Gilst, Marc R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325191/
https://www.ncbi.nlm.nih.gov/pubmed/22511885
http://dx.doi.org/10.1371/journal.pgen.1002645
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author Pathare, Pranali P.
Lin, Alex
Bornfeldt, Karin E.
Taubert, Stefan
Van Gilst, Marc R.
author_facet Pathare, Pranali P.
Lin, Alex
Bornfeldt, Karin E.
Taubert, Stefan
Van Gilst, Marc R.
author_sort Pathare, Pranali P.
collection PubMed
description Mammalian nuclear receptors broadly influence metabolic fitness and serve as popular targets for developing drugs to treat cardiovascular disease, obesity, and diabetes. However, the molecular mechanisms and regulatory pathways that govern lipid metabolism remain poorly understood. We previously found that the Caenorhabditis elegans nuclear hormone receptor NHR-49 regulates multiple genes in the fatty acid beta-oxidation and desaturation pathways. Here, we identify additional NHR-49 targets that include sphingolipid processing and lipid remodeling genes. We show that NHR-49 regulates distinct subsets of its target genes by partnering with at least two other distinct nuclear receptors. Gene expression profiles suggest that NHR-49 partners with NHR-66 to regulate sphingolipid and lipid remodeling genes and with NHR-80 to regulate genes involved in fatty acid desaturation. In addition, although we did not detect a direct physical interaction between NHR-49 and NHR-13, we demonstrate that NHR-13 also regulates genes involved in the desaturase pathway. Consistent with this, gene knockouts of these receptors display a host of phenotypes that reflect their gene expression profile. Our data suggest that NHR-80 and NHR-13's modulation of NHR-49 regulated fatty acid desaturase genes contribute to the shortened lifespan phenotype of nhr-49 deletion mutant animals. In addition, we observed that nhr-49 animals had significantly altered mitochondrial morphology and function, and that distinct aspects of this phenotype can be ascribed to defects in NHR-66– and NHR-80–mediated activities. Identification of NHR-49's binding partners facilitates a fine-scale dissection of its myriad regulatory roles in C. elegans. Our findings also provide further insights into the functions of the mammalian lipid-sensing nuclear receptors HNF4α and PPARα.
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spelling pubmed-33251912012-04-17 Coordinate Regulation of Lipid Metabolism by Novel Nuclear Receptor Partnerships Pathare, Pranali P. Lin, Alex Bornfeldt, Karin E. Taubert, Stefan Van Gilst, Marc R. PLoS Genet Research Article Mammalian nuclear receptors broadly influence metabolic fitness and serve as popular targets for developing drugs to treat cardiovascular disease, obesity, and diabetes. However, the molecular mechanisms and regulatory pathways that govern lipid metabolism remain poorly understood. We previously found that the Caenorhabditis elegans nuclear hormone receptor NHR-49 regulates multiple genes in the fatty acid beta-oxidation and desaturation pathways. Here, we identify additional NHR-49 targets that include sphingolipid processing and lipid remodeling genes. We show that NHR-49 regulates distinct subsets of its target genes by partnering with at least two other distinct nuclear receptors. Gene expression profiles suggest that NHR-49 partners with NHR-66 to regulate sphingolipid and lipid remodeling genes and with NHR-80 to regulate genes involved in fatty acid desaturation. In addition, although we did not detect a direct physical interaction between NHR-49 and NHR-13, we demonstrate that NHR-13 also regulates genes involved in the desaturase pathway. Consistent with this, gene knockouts of these receptors display a host of phenotypes that reflect their gene expression profile. Our data suggest that NHR-80 and NHR-13's modulation of NHR-49 regulated fatty acid desaturase genes contribute to the shortened lifespan phenotype of nhr-49 deletion mutant animals. In addition, we observed that nhr-49 animals had significantly altered mitochondrial morphology and function, and that distinct aspects of this phenotype can be ascribed to defects in NHR-66– and NHR-80–mediated activities. Identification of NHR-49's binding partners facilitates a fine-scale dissection of its myriad regulatory roles in C. elegans. Our findings also provide further insights into the functions of the mammalian lipid-sensing nuclear receptors HNF4α and PPARα. Public Library of Science 2012-04-12 /pmc/articles/PMC3325191/ /pubmed/22511885 http://dx.doi.org/10.1371/journal.pgen.1002645 Text en Pathare et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Pathare, Pranali P.
Lin, Alex
Bornfeldt, Karin E.
Taubert, Stefan
Van Gilst, Marc R.
Coordinate Regulation of Lipid Metabolism by Novel Nuclear Receptor Partnerships
title Coordinate Regulation of Lipid Metabolism by Novel Nuclear Receptor Partnerships
title_full Coordinate Regulation of Lipid Metabolism by Novel Nuclear Receptor Partnerships
title_fullStr Coordinate Regulation of Lipid Metabolism by Novel Nuclear Receptor Partnerships
title_full_unstemmed Coordinate Regulation of Lipid Metabolism by Novel Nuclear Receptor Partnerships
title_short Coordinate Regulation of Lipid Metabolism by Novel Nuclear Receptor Partnerships
title_sort coordinate regulation of lipid metabolism by novel nuclear receptor partnerships
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325191/
https://www.ncbi.nlm.nih.gov/pubmed/22511885
http://dx.doi.org/10.1371/journal.pgen.1002645
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