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Identification of Cholestenoic Acid as a Ligand for the Nuclear Hormone Receptor DAF-12 in Caenorhabditis Elegans

出版	University of California, San Francisco, 2006
ISBN	05427087959780542708794
URL	http://books.google.com.hk/books?id=uGVfrBJcErYC&hl=&source=gbs_api

註釋The orphan nuclear DAF-12 regulates C. elegans dauer formation, lipid metabolism, and lifespan in response to the environmental cues of population density, temperature, and food availability. The identity of the DAF-12 1igand has not yet been discovered despite significant evidence that it is sterol-derived and metabolized by DAF-9, a cytochrome P450. We have previously identified that lipophilic nematode extracts can rescue dauer formation in C. elegans. Chemical characterizations of these extracts demonstrate that the ligand for DAF-12 contains a carboxyl moiety and we show that C. elegans can carboxylate sterols. A candidate ligand screen of sterol acids found that the C27 bile acid cholestenoic acid (5-cholesten-3beta-ol-(25S)-carboxylic acid) promotes reproductive growth in dauer-constitutive mutants in a daf-9 and daf-12 dependent manner by acting as a DAF-12 ligand. Gas chromatography-mass spectrometry analysis of the dauer-rescuing lipophilic extracts identified several regioisomers of cholestenoic acid that are not present in extracts from hormone deficient daf-9 mutants. These findings confirm an endocrine link between DAF-12 and upstream signaling pathways that regulate dauer formation and lifespan determination. Identification of cholestenoic acid provides an important tool to further decipher the mechanism of these phenotypes and suggests that carboxylated sterols play an important role in the life history of C. elegans.