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Related Experiment Videos

ATF6 modulates SREBP2-mediated lipogenesis.

Lingfang Zeng1, Min Lu, Kazutoshi Mori

  • 1Division of Biomedical Sciences, University of California, Riverside, Riverside, CA 92521-0121, USA.

The EMBO Journal
|February 7, 2004
PubMed
Summary
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Glucose deprivation activates ATF6, inhibiting SREBP2 and lipogenesis. ATF6 antagonizes SREBP2 via direct binding, revealing a novel mechanism for lipid and glucose homeostasis regulation.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Metabolic Regulation

Background:

  • Activating transcription factor 6 (ATF6) and sterol regulatory element-binding proteins (SREBPs) are key transcription factors regulating cellular stress and lipid metabolism, respectively.
  • Both ATF6 and SREBPs are activated by proteolytic cleavage, leading to nuclear translocation of their functional N-terminal domains.

Purpose of the Study:

  • To investigate the interplay between ATF6 and SREBP2 signaling pathways under glucose deprivation.
  • To elucidate the molecular mechanism by which ATF6 influences SREBP2-mediated lipogenesis.

Main Methods:

  • Utilized cell culture models and molecular biology techniques including overexpression, gene cleavage blockade, GST pull-down, immunoprecipitation, and chromatin immunoprecipitation assays.
  • Analyzed the effects of ATF6 on SREBP2-regulated gene transcription and lipogenesis in liver cells.

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Main Results:

  • Glucose deprivation activated ATF6 but suppressed SREBP2-regulated transcription.
  • Overexpression of ATF6 N-terminus (ATF6(N)) inhibited SREBP2 target genes and lipogenesis, an effect reversed by blocking ATF6 cleavage.
  • ATF6(N) directly bound to SREBP2 N-terminus (SREBP2(N)) via ATF6's leucine-zipper domain, forming a complex that recruited HDAC1, thereby attenuating SREBP2 transcriptional activity.

Conclusions:

  • ATF6 antagonizes SREBP2 activity through direct physical interaction and recruitment of HDAC1, leading to suppression of lipogenesis.
  • This study reveals a novel regulatory mechanism where ATF6 modulates SREBP2 function to maintain lipid and glucose homeostasis.