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

被引:327
作者
BENNETT, MK [1 ]
LOPEZ, JM [1 ]
SANCHEZ, HB [1 ]
OSBORNE, TF [1 ]
机构
[1] UNIV CALIF IRVINE,DEPT MOLEC BIOL & BIOCHEM,IRVINE,CA 92717
关键词
D O I
10.1074/jbc.270.43.25578
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The gene encoding fatty acid synthase, the essential multi-functional enzyme of fatty acid biosynthesis, is shown to be regulated by cellular sterol levels similar to genes that encode important proteins of cholesterol metabolism. me show that expression of the endogenous FAS gene is repressed when regulatory sterols are included in the culture medium of HepG2 cells and that the FAS promoter is subject to similar regulation when fused to the luciferase reporter gene. Mutational studies demonstrate that sterol regulation is mediated by binding sites for the 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 that SREBP and Sp1 synergistically activate the FAS promoter in Drosophila tissue culture cells, which lack endogenous Sp1. These experiments provide key molecular evidence that directly links the metabolism of fatty acids and cholesterol together.
引用
收藏
页码:25578 / 25583
页数:6
相关论文
共 28 条
  • [1] MOLECULAR-CLONING OF THE MAMMALIAN FATTY-ACID SYNTHASE GENE AND IDENTIFICATION OF THE PROMOTER REGION
    AMY, CM
    WILLIAMSAHLF, B
    NAGGERT, J
    SMITH, S
    [J]. BIOCHEMICAL JOURNAL, 1990, 271 (03) : 675 - 679
  • [2] MOLECULAR-CLONING AND SEQUENCING OF CDNAS ENCODING THE ENTIRE RAT FATTY-ACID SYNTHASE
    AMY, CM
    WITKOWSKI, A
    NAGGERT, J
    WILLIAMS, B
    RANDHAWA, Z
    SMITH, S
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (09) : 3114 - 3118
  • [3] BRIGGS MR, 1993, J BIOL CHEM, V268, P14490
  • [4] A RECEPTOR-MEDIATED PATHWAY FOR CHOLESTEROL HOMEOSTASIS
    BROWN, MS
    GOLDSTEIN, JL
    [J]. SCIENCE, 1986, 232 (4746) : 34 - 47
  • [5] ISOLATION OF BIOLOGICALLY-ACTIVE RIBONUCLEIC-ACID FROM SOURCES ENRICHED IN RIBONUCLEASE
    CHIRGWIN, JM
    PRZYBYLA, AE
    MACDONALD, RJ
    RUTTER, WJ
    [J]. BIOCHEMISTRY, 1979, 18 (24) : 5294 - 5299
  • [6] ANALYSIS OF SP1 INVIVO REVEALS MULTIPLE TRANSCRIPTIONAL DOMAINS, INCLUDING A NOVEL GLUTAMINE-RICH ACTIVATION MOTIF
    COUREY, AJ
    TJIAN, R
    [J]. CELL, 1988, 55 (05) : 887 - 898
  • [7] DAWSON PA, 1988, J BIOL CHEM, V263, P3372
  • [8] THE PROMOTER-SPECIFIC TRANSCRIPTION FACTOR-SP1 BINDS TO UPSTREAM SEQUENCES IN THE SV40 EARLY PROMOTER
    DYNAN, WS
    TJIAN, R
    [J]. CELL, 1983, 35 (01) : 79 - 87
  • [9] Glickman R.M., 1988, LIVER BIOL PATHOBIOL, V2nd, P331
  • [10] GOLDSTEIN JL, 1983, METHOD ENZYMOL, V98, P241