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Antidiabetic actions of a phosphatidylcholine ligand for nuclear receptor LRH-1

Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (NR5A2) regulates bile acid biosynthesis(1,2). Structural studies have identified phospholipids as potential LRH-1 ligands(3–5), but their functional relevance is unclear. Here we show that an unusual...

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Autores principales: Lee, Jae Man, Lee, Yoon Kwang, Mamrosh, Jennifer L., Busby, Scott A., Griffin, Patrick R., Pathak, Manish C., Ortlund, Eric A., Moore, David D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150801/
https://www.ncbi.nlm.nih.gov/pubmed/21614002
http://dx.doi.org/10.1038/nature10111
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author Lee, Jae Man
Lee, Yoon Kwang
Mamrosh, Jennifer L.
Busby, Scott A.
Griffin, Patrick R.
Pathak, Manish C.
Ortlund, Eric A.
Moore, David D.
author_facet Lee, Jae Man
Lee, Yoon Kwang
Mamrosh, Jennifer L.
Busby, Scott A.
Griffin, Patrick R.
Pathak, Manish C.
Ortlund, Eric A.
Moore, David D.
author_sort Lee, Jae Man
collection PubMed
description Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (NR5A2) regulates bile acid biosynthesis(1,2). Structural studies have identified phospholipids as potential LRH-1 ligands(3–5), but their functional relevance is unclear. Here we show that an unusual phosphatidylcholine species with two saturated 12 carbon fatty acid acyl side chains (dilauroyl phosphatidylcholine, DLPC) is an LRH-1 agonist ligand in vitro. DLPC treatment induces bile acid biosynthetic enzymes in mouse liver, increases bile acid levels, and lowers hepatic triglycerides and serum glucose. DLPC treatment also decreases hepatic steatosis and improves glucose homeostasis in two mouse models of insulin resistance. Both the antidiabetic and lipotropic effects are lost in liver specific Lrh-1 knockouts. These findings identify an LRH-1 dependent phosphatidylcholine signaling pathway that regulates bile acid metabolism and glucose homeostasis.
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spelling pubmed-31508012011-12-23 Antidiabetic actions of a phosphatidylcholine ligand for nuclear receptor LRH-1 Lee, Jae Man Lee, Yoon Kwang Mamrosh, Jennifer L. Busby, Scott A. Griffin, Patrick R. Pathak, Manish C. Ortlund, Eric A. Moore, David D. Nature Article Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (NR5A2) regulates bile acid biosynthesis(1,2). Structural studies have identified phospholipids as potential LRH-1 ligands(3–5), but their functional relevance is unclear. Here we show that an unusual phosphatidylcholine species with two saturated 12 carbon fatty acid acyl side chains (dilauroyl phosphatidylcholine, DLPC) is an LRH-1 agonist ligand in vitro. DLPC treatment induces bile acid biosynthetic enzymes in mouse liver, increases bile acid levels, and lowers hepatic triglycerides and serum glucose. DLPC treatment also decreases hepatic steatosis and improves glucose homeostasis in two mouse models of insulin resistance. Both the antidiabetic and lipotropic effects are lost in liver specific Lrh-1 knockouts. These findings identify an LRH-1 dependent phosphatidylcholine signaling pathway that regulates bile acid metabolism and glucose homeostasis. 2011-05-25 /pmc/articles/PMC3150801/ /pubmed/21614002 http://dx.doi.org/10.1038/nature10111 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Lee, Jae Man
Lee, Yoon Kwang
Mamrosh, Jennifer L.
Busby, Scott A.
Griffin, Patrick R.
Pathak, Manish C.
Ortlund, Eric A.
Moore, David D.
Antidiabetic actions of a phosphatidylcholine ligand for nuclear receptor LRH-1
title Antidiabetic actions of a phosphatidylcholine ligand for nuclear receptor LRH-1
title_full Antidiabetic actions of a phosphatidylcholine ligand for nuclear receptor LRH-1
title_fullStr Antidiabetic actions of a phosphatidylcholine ligand for nuclear receptor LRH-1
title_full_unstemmed Antidiabetic actions of a phosphatidylcholine ligand for nuclear receptor LRH-1
title_short Antidiabetic actions of a phosphatidylcholine ligand for nuclear receptor LRH-1
title_sort antidiabetic actions of a phosphatidylcholine ligand for nuclear receptor lrh-1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150801/
https://www.ncbi.nlm.nih.gov/pubmed/21614002
http://dx.doi.org/10.1038/nature10111
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