TY - JOUR
T1 - Multiple regulatory layers of SREBP1/2 by SIRT6
AU - Elhanati, Sivan
AU - Kanfi, Yariv
AU - Varvak, Alexander
AU - Roichman, Asael
AU - Carmel-Gross, Ilana
AU - Barth, Shaul
AU - Gibor, Gilad
AU - Cohen, Haim Y.
N1 - Funding Information:
We thank the members of the Cohen lab and Dr. Shelley Schwarzbaum for their helpful comments on the manuscript. This study was supported by the Israel Science Foundation, I-Core Foundation, Israeli Ministry of Health, and the ERC: European Research Council. H.C. is a consultant to SIRTLab, a company developing sirtuin-based therapy.
PY - 2013/5/12
Y1 - 2013/5/12
N2 - 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
AB - 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
UR - http://www.scopus.com/inward/record.url?scp=84884150671&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2013.08.006
DO - 10.1016/j.celrep.2013.08.006
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C2 - 24012758
AN - SCOPUS:84884150671
SN - 2211-1247
VL - 4
SP - 905
EP - 912
JO - Cell Reports
JF - Cell Reports
IS - 5
ER -