Multiple regulatory layers of SREBP1/2 by SIRT6

Sivan Elhanati, Yariv Kanfi, Alexander Varvak, Asael Roichman, Ilana Carmel-Gross, Shaul Barth, Gilad Gibor, Haim Y. Cohen

Research output: Contribution to journalArticlepeer-review

133 Scopus citations

Abstract

The NAD+-dependent protein deacetylase SIRT6 regulates genome stability, cancer, and lifespan. Mice overexpressing SIRT6 (MOSES) have lower low-density lipoprotein cholesterol levels and are protected against the physiological damage of obesity. Here, we examined the role of SIRT6 in cholesterol regulation via the lipogenic transcription factors SREBP1 and SREBP2, and AMP-activated protein kinase (AMPK). We show that SIRT6 represses SREBP1 and SREBP2 by at least three mechanisms. First, SIRT6 represses the transcription levels of SREBP1/SREBP2 and that of their target genes. Second, SIRT6 inhibits the cleavage of SREBP1/SREBP2 into their active forms. Third, SIRT6 activates AMPK by increasing the AMP/ATP ratio, which promotes phosphorylation and inhibition of SREBP1 by AMPK. Reciprocally, the expression of miR33a and miR33b from the introns of SREBP2 and SREBP1, respectively, represses SIRT6 levels. Together, these findings explain the mechanism underlying the improved cholesterol homeostasis in MOSES mice, revealing a relationship between fat metabolism and longevity

Original languageEnglish
Pages (from-to)905-912
Number of pages8
JournalCell Reports
Volume4
Issue number5
DOIs
StatePublished - 12 May 2013
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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