Nuclear receptor in the crosshairs of diabetes
Researchers at the Baylor College of Medicine and Scripps Florida have identified a new signaling pathway that could be targeted to treat type 2 diabetes.1 The group has shown that activating the nuclear receptor LRH-1 pathway in mice can decrease fatty liver and increase insulin sensitivity without the typical weight gain caused by marketed PPAR agonists. The group's collaborators are running a pilot trial in prediabetic individuals to evaluate one LRH-1 agonist-dilauroyl phosphatidylcholine.
LRH-1 (nuclear receptor subfamily 5 group A member 2; NR5A2) is an orphan nuclear receptor best known for its role as a regulator of bile acid synthesis.2 Because high levels of bile acids in the liver are known to reduce fatty liver3 and improve glucose homeostasis,4 the BCM and Scripps team began a search for compounds that activate LRH-1.
Previous reports had also shown that LRH-1 could potentially interact with phospholipids,5,6 which led the researchers to focus their screening efforts on phospholipids that activated LRH-1.
Those screens turned up a pair of phospholipids-dilauroyl phosphatidylcholine (DLPC) and diundecanoyl phosphatidylcholine (DUPC)-as potent activators of LRH-1 signaling. Although