Cell Metabolism n e

, Udomain (LBD) that can impart multiple functions, including hormone binding, receptor dimerization, and transactivation. Nuclear receptors are regulated by a wide range of lipophilic compounds that include dietary signals and metabolic interme-diates, such as sterols, fatty acids, and bile acids. Binding of these compounds to the LBD triggers a conformational change that switches the regulatory function of the receptor, directing coordinate changes in downstream target gene expression. The resulting transcriptional programs often drive feedback or feed-forward pathways that act upon the specific class of compounds bound by the receptor (Chawla et al., 2001). Func-tional studies of several nuclear receptor subclasses, including the expression of 65 genes involved in energymetabolism, signif-icant effects were observed in mitochondrial b-oxidation, the pathway by which fatty acids are utilized for energy production, and fatty acid desaturation, increasing the ratio of stearic acid to oleic acid inmutant worms. Overexpression of amitochondrial acyl-CoA synthetase that is downregulated in nhr-49 mutants was sufficient to suppress the high-fat phenotype, suggesting that this defect arises from reduced levels of b-oxidation. Biochemical studies have provided insights into the molecular mechanisms of HNF4 function. The basal transcriptional activity of HNF4 can be enhanced by fatty acyl-CoA thioesters, suggest-ing that HNF4 may be modulated by a fatty acid-derived ligandDrosophila HNF4 Regulates Lipid Mobilization and b-O