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.

Astragaloside IV sensitizes non–small cell lung cancer cells to gefitinib potentially via regulation of SIRT6

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DNA damage responsive miR-33b-3p promoted lung cancer cells survival and cisplatin resistance by targeting p21WAF1/CIP1

“…42 SIRT6, similar as NFkB, was a stress-responsive chromatin modifier, which shaped stress -related transcriptional networks. 43 Thus, we speculated that the down-regulation of miR-33b-3p by cisplatin treatment might probably through the SIRT6-mediated deacetylation in the promoter as well.…”

Biosynthesis of milk fat, protein, and lactose: roles of transcriptional and posttranscriptional regulation

“…However, a role for prolactin and serine/threonine protein kinase AKT1 in controlling the expression of SREBF1 was suggested (4). Additionally, the energy level in the diet may affect expression of SREBF1 as indicated by a recent study in mouse (68).…”