The C. elegans NHR-49 is a lipid sensing nuclear receptor that has been shown to orchestrate multiple aspects of fat homeostasis, including mitochondrial <font face=symbol>b</font>-oxidation and fatty acid desaturation. To more comprehensively define the targets of NHR-49, we exploited global gene expression profiling. These experiments revealed a previously uncharacterized role for NHR-49 in the regulation of genes involved in membrane lipid metabolism, particularly glycosphingolipid processing. Indeed, deletion of
nhr-49 resulted in dramatically increased expression of several sphingolipid (SL) metabolism genes, as well as other factors likely to influence phospholipid processing. Sphingolipids are important structural components of cell membranes as well as potent signaling molecules implicated in apoptosis, cell division and differentiation. However, little is known about the transcription factors that control SL gene expression. Consistent with NHR-49s impact on SL metabolism genes, biochemical analysis revealed a significantly altered sphingolipid profile in
nhr-49 knockout mutants. Therefore, our findings reveal a new role for NHR-49 in the control of sphingolipid composition. Two hybrid studies have found that NHR-49 can bind to many different C. elegans NHRs1. Since nuclear receptors often regulate gene expression by forming heterodimers, we examined these potential binding partners to determine if they impacted NHR-49 gene regulation. Notably, we found that knockout of
nhr-66 affected only a subset of NHR-49 targets. In particular,
nhr-66 was exclusively required for the repression of NHR-49s sphingolipid and phospholipid metabolism targets. In contrast, deletion of
nhr-66 did not impact NHR-49 activation of <font face=symbol>b</font>-oxidation and fatty acid desaturation genes. Thus, our findings support a model whereby NHR-49 and NHR-66 heterodimerize to mediate the repression of genes involved in membrane lipid composition. Therefore, NHR-49 independently regulates multiple lipid metabolism pathways, and the distinct lipid metabolism networks targeted by NHR-49 are determined by dimerization with different NHR partners. (1)Taubert S, Van Gilst M, Hansen M, and Yamamoto KR. (2006) Genes Dev 20, 1137-1149.