Recent x-ray crystal studies have identified phospholipids as potential ligands, but their relevance to LRH-1 transactivation has been unclear. We have found that unusual phosphatidylcholine (PC) species with two C11:0 (diundecanoyl;DUPC) or two C12:0 (dilauroyl;DLPC) fatty acid side chains are potent activators of LRH-1 transactivation. Both compounds are agonists that increase coactivator binding both in vitro and in cells. In preliminary studies, treatment of mice with either DUPC or DLPC induces expression of bile acid biosynthetic enzymes and increases overall bile acid pool size. DLPC treatment also markedly improves glucose homeostasis in diabetic db/db mice. The goal of this proposal is to test the hypothesis that LRH-1 is a key metabolic regulator with agonist ligands that have beneficial effects in metabolic disorders. The aims are to: 1. Define the impact of novel LRH-1 agonist ligands on gene expression and function in cultured hepatocytes and intestinal cell lines. 2. Define the impact of novel LRH-1 agonist ligands on gene expression and function in normal mouse liver and intestine. 3. Define the impact of novel LRH-1 ligands on gene expression and function in murine disease models, particularly type 2 diabetes and inflammatory bowel disease. We believe that these studies will produce new insights into metabolic homeostasis, and that they have the potential to open up a completely new avenue to approaching metabolic disorders. PUBLIC HEALTH RELEVANCE: This project is based on the discovery of a new class of potential hormones. These compounds activate two poorly understood nuclear hormone receptors and alter liver functions. They also show antidiabetic effects, and a particular goal is to explore how they work and whether they have potential therapeutic utility.

R01DK083572

2009-07-20

2011-06-30