Unsaturated fatty acids inhibit transcription of the sterol regulatory element-binding protein-1c (SREBP-1c) gene by antagonizing ligand-dependent activation of the LXR

Sterol regulatory element-binding protein-lc (SREBP-1c) enhances transcript ion of genes encoding enzymes of unsaturated fatty acid biosynthesis in liv er. SREBP-1c mRNA is known to increase when cells are treated with agonists of liver X receptor (LXR), a nuclear hormone receptor, and to decrease whe n cells are treated with unsaturated fatty acids, the end products of SREBP -1c action. Here we show that unsaturated fatty acids lower SREBP-1c mRNA l evels in part by antagonizing the actions of LXR. In cultured rat hepatoma cells, arachidonic acid and other fatty acids competitively inhibited activ ation of the endogenous SREBP-1c gene by an LXR ligand. Arachidonate also b locked the activation of a synthetic LXR-dependent promoter in transfected human embryonic kidney-293 cells. In vitro, arachidonate and other unsatura ted fatty acids competitively blocked activation of LXR, as reflected by a fluorescence polarization assay that measures ligand-dependent binding of L XR to a peptide derived from a coactivator. These data offer a potential me chanism that partially explains the long-known ability of dietary unsaturat ed fatty acids to decrease the synthesis and secretion of fatty acids and t riglycerides in livers of humans and other animals.