STEROL REGULATION OF FATTY-ACID SYNTHASE PROMOTER - COORDINATE FEEDBACK-REGULATION OF 2 MAJOR LIPID PATHWAYS

The gene encoding fatty acid synthase, the essential multi-functional enzyme of fatty acid biosynthesis, is shown to be regulated by cellula r sterol levels similar to genes that encode important proteins of cho lesterol metabolism. me show that expression of the endogenous FAS gen e is repressed when regulatory sterols are included in the culture med ium of HepG2 cells and that the FAS promoter is subject to similar reg ulation when fused to the luciferase reporter gene. Mutational studies demonstrate that sterol regulation is mediated by binding sites for t he sterol regulatory element-binding protein (SREBP) and transcription factor Sp1, making it mechanistically similar to sterol regulation of the low density lipoprotein receptor gene. It is also demonstrated th at SREBP and Sp1 synergistically activate the FAS promoter in Drosophi la tissue culture cells, which lack endogenous Sp1. These experiments provide key molecular evidence that directly links the metabolism of f atty acids and cholesterol together.