OLEATE POTENTIATES OXYSTEROL INHIBITION OF TRANSCRIPTION FROM STEROL REGULATORY ELEMENT-1-REGULATED PROMOTERS AND MATURATION OF STEROL REGULATORY ELEMENT-BINDING PROTEINS

Activation of genes containing SRE-1 (sterol regulatory element 1) seq uences is known to be under the regulation of sterols through modulati on of the proteolytic maturation of SREBPs (SRE-1-binding proteins). P revious work has demonstrated SREBP-mediated transcriptional activatio n of genes encoding enzymes of sterol and fatty acid biosynthesis. Bec ause synthesis of both sterols and C18 fatty acids are required for ce ll growth, in the absence of exogenous supplements of these lipids, we examined the hypothesis that fatty acid can also be regulatory in SRE BP maturation. Our data indicate that C18 fatty acids can potentiate t he biological activities of a typical, regulatory sterol: 25-hydroxych olesterol. Inhibition of C18 fatty acid synthesis in cells cultured in serum-free medium renders them resistant to killing by 25-hydroxychol esterol. Repression of expression of reporter constructs driven by pro moters bearing SRE-1 element(s) by 25-hydroxycholesterol is increased by C18 fatty acid supplementation. C18 fatty acids also increase the i nhibitory effect of 25-hydroxycholesterol on proteolytic maturation an d nuclear localization of SREBPs, Furthermore, we also show that C18 f atty acid supplementation can enhance the inhibitory effect of 25-hydr oxycholesterol on sterol and fatty acid biosynthesis, These results de monstrate that maximal down-regulation of SREBP maturation and the con sequent repression of SRE-1 promoters occurs in response to both a reg ulatory sterol and fatty acid.