Mk. Bennett et al., STEROL REGULATION OF FATTY-ACID SYNTHASE PROMOTER - COORDINATE FEEDBACK-REGULATION OF 2 MAJOR LIPID PATHWAYS, The Journal of biological chemistry, 270(43), 1995, pp. 25578-25583
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.