Multiple Regulatory Layers of SREBP1/2 by SIRT6

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 re...

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Main Authors: Sivan Elhanati, Yariv Kanfi, Alexander Varvak, Asael Roichman, Ilana Carmel-Gross, Shaul Barth, Gilad Gibor, Haim Y. Cohen
Format: Article
Language:English
Published: Elsevier 2013-09-01
Series:Cell Reports
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124713004300
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spelling doaj-40ec652d95a4433f8056d09c69c5ae2b2020-11-25T00:20:06ZengElsevierCell Reports2211-12472013-09-014590591210.1016/j.celrep.2013.08.006Multiple Regulatory Layers of SREBP1/2 by SIRT6Sivan Elhanati0Yariv Kanfi1Alexander Varvak2Asael Roichman3Ilana Carmel-Gross4Shaul Barth5Gilad Gibor6Haim Y. Cohen7The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, IsraelThe Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, IsraelThe Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, IsraelThe Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, IsraelThe Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, IsraelThe Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, IsraelThe Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, IsraelThe Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel 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. http://www.sciencedirect.com/science/article/pii/S2211124713004300
collection DOAJ
language English
format Article
sources DOAJ
author Sivan Elhanati
Yariv Kanfi
Alexander Varvak
Asael Roichman
Ilana Carmel-Gross
Shaul Barth
Gilad Gibor
Haim Y. Cohen
spellingShingle Sivan Elhanati
Yariv Kanfi
Alexander Varvak
Asael Roichman
Ilana Carmel-Gross
Shaul Barth
Gilad Gibor
Haim Y. Cohen
Multiple Regulatory Layers of SREBP1/2 by SIRT6
Cell Reports
author_facet Sivan Elhanati
Yariv Kanfi
Alexander Varvak
Asael Roichman
Ilana Carmel-Gross
Shaul Barth
Gilad Gibor
Haim Y. Cohen
author_sort Sivan Elhanati
title Multiple Regulatory Layers of SREBP1/2 by SIRT6
title_short Multiple Regulatory Layers of SREBP1/2 by SIRT6
title_full Multiple Regulatory Layers of SREBP1/2 by SIRT6
title_fullStr Multiple Regulatory Layers of SREBP1/2 by SIRT6
title_full_unstemmed Multiple Regulatory Layers of SREBP1/2 by SIRT6
title_sort multiple regulatory layers of srebp1/2 by sirt6
publisher Elsevier
series Cell Reports
issn 2211-1247
publishDate 2013-09-01
description 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.
url http://www.sciencedirect.com/science/article/pii/S2211124713004300
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