title: Multiple regulatory layers of SREBP1/2 by SIRT6.
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.
authors.affiliation: The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
authors.forename: Sivan
authors.initials: S
authors.lastname: Elhanati
authors.forename: Yariv
authors.initials: Y
authors.lastname: Kanfi
authors.forename: Alexander
authors.initials: A
authors.lastname: Varvak
authors.forename: Asael
authors.initials: A
authors.lastname: Roichman
authors.forename: Ilana
authors.initials: I
authors.lastname: Carmel-Gross
authors.forename: Shaul
authors.initials: S
authors.lastname: Barth
authors.forename: Gilad
authors.initials: G
authors.lastname: Gibor
authors.forename: Haim Y
authors.initials: HY
authors.lastname: Cohen
mesh_terms: D036002:ADP Ribose Transferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D010766:Phosphorylation; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D036002:ADP Ribose Transferases; C501860:Sirt6 protein, mouse; C516592:SIRT6 protein, human; D037761:Sirtuins