A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects

Jae Man Lee; Yoon Kwang Lee; Jennifer L. Mamrosh; Scott A. Busby; Patrick R. Griffin; Manish C. Pathak; Eric A. Ortlund; David D. Moore

doi:10.1038/nature10111

A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects

Jae Man Lee, Yoon Kwang Lee, Jennifer L. Mamrosh, Scott A. Busby, Patrick R. Griffin, Manish C. Pathak, Eric A. Ortlund, David D. Moore

Research output: Contribution to journal › Article › peer-review

193 Scopus citations

Abstract

Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as 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 signalling pathway that regulates bile acid metabolism and glucose homeostasis.

Original language	English
Pages (from-to)	506-511
Number of pages	6
Journal	Nature
Volume	474
Issue number	7352
DOIs	https://doi.org/10.1038/nature10111
State	Published - 23 Jun 2011

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abstract = "Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis1,2. Structural studies have identified phospholipids as potential LRH-1 ligands3-5, 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 signalling pathway that regulates bile acid metabolism and glucose homeostasis.",

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AU - Lee, Jae Man

AU - Lee, Yoon Kwang

AU - Mamrosh, Jennifer L.

AU - Busby, Scott A.

AU - Griffin, Patrick R.

AU - Pathak, Manish C.

AU - Ortlund, Eric A.

AU - Moore, David D.

PY - 2011/6/23

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AB - Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis1,2. Structural studies have identified phospholipids as potential LRH-1 ligands3-5, 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 signalling pathway that regulates bile acid metabolism and glucose homeostasis.

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A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects

Abstract

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