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 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. [Display omitted] •SIRT6 overexpression results in reduced cholesterol and triglyceride levels•SIRT6 inhibits SREBP1 and SREBP2 by blocking their expression and processing•SIRT6 inhibits SREBP1 by activating AMPK via increased AMP/ATP ratio•SIRT6 and SREBP1/ SREBP2 are reciprocally regulated In addition to having an extended lifespan, mice overexpressing SIRT6 have improved lipid homeostasis. Here, Cohen and colleagues explore the mechanisms underlying this phenomenon. They show that SIRT6 suppresses the activity and cleavage activation of the lipogenic transcription factors SREBP1 and SREBP2 via several pathways: reducing the levels of their proteolytic complex, stimulating their inhibitory phosphorylation by AMPK, and repressing the transcription levels of SREBP target genes. Together, these findings suggest a relationship between fat metabolism and longevity.