Nuclear receptor regulation of the fatty acid synthase promoter

Both thyroid hormone receptor (TR) and liver x receptor (LXR) bind to a common DNA element in the fatty acid synthase (FAS) promoter known as a d&barbelow;irect r&barbelow;epeat spaced by four nucleotides, or DR-4. Despite this shared binding site, TR and LXR have many distinct features of their mechanisms of FAS promoter activation. We demonstrate that a nuclear receptor half-site 21 bases downstream from the DR-4 is important for both TR and LXR activation of FAS but while important for RXR/TR binding to this region of the promoter, it does not bind RXR/LXR. We demonstrate that another nuclear receptor known as LRH-1 (liver receptor homolog-1) binds to the this half-site and functions to potentiate RXR/LXR but not RXR/TR signaling. Our promoter studies also reveal that TR has an absolute requirement for an NF-Y binding site in the proximal promoter of FAS for T3 dependent activation whereas oxysterol/LXR activation of FAS does not.; One mechanism by which bile acids mediate transcriptional events is by serving as low affinity ligands for the nuclear receptor farnesoid X receptor (FXR). We have identified a novel target of FXR signaling by demonstrating binding and activation of FAS by FXR/RXR heterodimers on a nuclear receptor element known as an i&barbelow;nverted r&barbelow;epeat separated by one nucleotide, or IR-1. We show that this site is responsive to activation by a synthetic FXR ligand, and mutation of either of the half-sites constituting the IR-1 abolishes this effect. Furthermore, mice fed a diet supplemented with 0.25% chenodeoxycholic acid, a bile acid and potent activator of FXR, show approximately three fold increased expression of FAS transcripts with respect to the control fed group.; The FXR/RXR binding site in the FAS promoter overlaps the binding site for LRH-1 that is involved in LXR signaling. This overlap in DNA binding is particularly interesting in that it may help to explain the bi-phasic response of FAS to elevated bile acid levels observed previously by others. Thus, our promoter studies provide significant new information on the mechanisms by which TR, LXR, and FXR specifically activate FAS transcription, and also provide a potential explanation for the complex physiology observed in animal studies.