Publication Date:
2011-05-27
Description:
Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis. Structural studies have identified phospholipids as potential LRH-1 ligands, 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 signalling pathway that regulates bile acid metabolism and glucose homeostasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150801/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150801/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Jae Man -- Lee, Yoon Kwang -- Mamrosh, Jennifer L -- Busby, Scott A -- Griffin, Patrick R -- Pathak, Manish C -- Ortlund, Eric A -- Moore, David D -- DK-079638/DK/NIDDK NIH HHS/ -- R01 CA134873/CA/NCI NIH HHS/ -- R01 DK068804/DK/NIDDK NIH HHS/ -- R01 DK083572/DK/NIDDK NIH HHS/ -- R01 DK083572-02/DK/NIDDK NIH HHS/ -- T32 DK007696/DK/NIDDK NIH HHS/ -- U54 MH084512/MH/NIMH NIH HHS/ -- England -- Nature. 2011 May 25;474(7352):506-10. doi: 10.1038/nature10111.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21614002" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Bile Acids and Salts/biosynthesis/metabolism/pharmacology
;
Blood Glucose/metabolism
;
Cell Line
;
Disease Models, Animal
;
Fatty Liver/drug therapy/enzymology
;
HeLa Cells
;
Homeostasis/drug effects
;
Humans
;
Hypoglycemic Agents/pharmacology
;
Insulin Resistance/physiology
;
Ligands
;
Lipogenesis/drug effects
;
Liver/drug effects/enzymology/metabolism
;
Male
;
Mice
;
Mice, Inbred C57BL
;
Mice, Knockout
;
Phosphatidylcholines/*metabolism/pharmacology
;
Protein Binding
;
Receptors, Cytoplasmic and Nuclear/agonists/deficiency/genetics/*metabolism
;
Signal Transduction/drug effects
;
Triglycerides/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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