The Emerging Role of SIRT7 in Glucose and Lipid Metabolism

Abstract

Sirtuins (SIRT1-7 in mammals) are a family of NAD+-dependent lysine deacetylases and deacylases that regulate diverse biological processes, including metabolism, stress responses, and aging. SIRT7 is the least well-studied member of the sirtuins, but accumulating evidence has shown that SIRT7 plays critical roles in the regulation of glucose and lipid metabolism by modulating many target proteins in white adipose tissue, brown adipose tissue, and liver tissue. This review focuses on the emerging roles of SIRT7 in glucose and lipid metabolism in comparison with SIRT1 and SIRT6. We also discuss the possible implications of SIRT7 inhibition in the treatment of metabolic diseases such as type 2 diabetes and obesity.

Keywords: SIRT1; SIRT6; SIRT7; diabetes; obesity; sirtuin.

Figure 2

Roles of SIRT7 in glucose metabolism. (A) SIRT7 stimulates gluconeogenesis through the destabilization of CRY1 [23]. (B) SIRT7 increases transcription of the gluconeogenic gene G6pc through the deacetylation of histone H3K18 [104]. (C) SIRT7 inhibits glycolysis by decreasing the HIF1 protein expression levels [109]. (D) SIRT7 also suppresses glycolysis through the deacetylation of PGK1 [25]. (E) SIRT7 deficiency increases energy expenditure by increasing the expression levels of the batokines Fgf21 and Nrg4 in BAT [21]. (F) SIRT7 suppresses AKT activation by deacetylating FKBP51 [26].

Figure 1

Roles of SIRT7 in lipid metabolism. (A) SIRT7 promotes adipogenesis by inhibiting SIRT1 and enhancing the activity of PPARγ [59]. (B) SIRT7 also promotes lipogenesis in WAT through the deacetylation of PPARγ2 [20]. (C) SIRT7 suppresses thermogenesis in BAT by deacetylating IMP2, an RNA-binding protein that inhibits the translation of Ucp1 mRNA [21]. (D) SIRT7 stimulates inflammation through the nuclear retention of the RAN-NF-κB complex. In the absence of SIRT7, acetylated RAN facilitates the formation of the NF-κB export cargo complex, thereby enhancing the nuclear exclusion of NF-κB [32]. (E) SIRT7 deacetylates DDB1, a component of CUL4B/DDB1/DCAF1 E3 ubiquitin ligase complex. SIRT7 increases TR4 protein expression and lipid accumulation in the liver by inhibiting the degradation of TR4 via the suppression of the E3 ubiquitin ligase complex [19]. (F) SIRT7 increases mitochondrial gene expression through the deacetylation of GABPβ1 [22].

Figure 3

Roles of SIRT1, SIRT6, and SIRT7 in metabolism. Comparison of the metabolic roles of SIRT1, SIRT6, and SIRT7. SIRT1 and SIRT6 stimulate lipolysis in WAT. In contrast, SIRT7 promotes lipogenesis in WAT. In addition, SIRT1 and SIRT6 stimulate thermogenesis in BAT, whereas SIRT7 inhibits it. Although SIRT1 and SIRT6 attenuate lipid accumulation in the liver, SIRT7 increases it. These observations indicate that SIRT7 regulates metabolism in opposite directions from SIRT1 and SIRT6 in some cases.