Feedback regulation of hepatic gluconeogenesis through modulation of SHP/Nr0b2 gene expression by Sirt1 and FoxO1

Abstract

Sirt1 has been implicated in the regulation of hepatic gluconeogenesis; however, the mechanisms are not fully understood. To further elucidate how Sirt1 regulates gluconeogenesis, we took a loss-offunction approach by deleting the coding DNA sequence for the catalytic domain of the Sirt1 gene in the liver of a wild-type mouse (LKO Sirt1 ) or a genetic diabetic mouse in which hepatic insulin receptor substrates 1 and 2 are deleted (DKO Irs1/2 ). Whereas LKO Sirt1 mice exhibited normal levels of fasting and fed blood glucose, inactivation of Sirt1 in DKO Irs1/2 mice (TKO Irs1/2:Sirt1 ) reduced blood glucose levels and moderately improved systemic glucose tolerance. Pyruvate tolerance was also significantly improved in TKO Irs1/2:Sirt1 mice, suggesting that Sirt1 promotes hepatic gluconeogenesis in this diabetic mouse model. To understand why inactivation of hepatic Sirt1 does not alter blood glucose levels in the wild-type background, we searched for a potential cause and found that expression of small heterodimer partner (SHP, encoded by the Nr0b2 gene), an orphan nuclear receptor, which has been shown to suppress the activity of forkhead transcription factor FoxO1, was decreased in the liver of LKO Sirt1 mice. Furthermore, our luciferase reporter assays and chromatin immunoprecipitation analysis revealed that the Nr0b2 gene is a target of FoxO1, which is also regulated by Sirt1. After the gene is upregulated, Nr0b2 can feed back and repress FoxO1-and Sirt1-activated G6pc and Pdk4 gene expression. Thus, our results suggest that Sirt1 can both positively and negatively regulate hepatic gluconeogenesis through FoxO1 and Nr0b2 and keep this physiological process in control.diabetes; insulin receptor substrate; small heterodimer partner; pyruvate dehydrogenase kinase-4

Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance

“…Of note, our finding that liver-specific disruption of SIRT1 increased gluconeogenesis is contradictory to previous studies of SIRT1 mutant mice, which did not report an obvious change in glucose production (18,20,21). We have considered whether this discrepancy could be caused by a difference in genetic background, as our Sirt1 ex5-6/ex5-6 ;Alb-Cre mice were in a mixed FVB/129/ Black Swiss genetic background, and the other Sirt1 ex4/ex4 ;Alb-Cre mice were in C57BL/6 genetic background.…”

“…In contrast, transgenic mice with moderate overexpression of SIRT1 displayed improved glucose tolerance due to decreased hepatic glucose production, suggesting a negative role of SIRT1 in gluconeogenesis (17). Moreover, a recent report using mice carrying a liver-specific deletion of exon 4 of the Sirt1 gene mediated by albumin-Cre (Sirt1 exon4/exon4 ;Alb-Cre mice) revealed normal levels of fasting and fed blood glucose (18). These observations may reflect a complex role of SIRT1 in the regulation of glucose metabolism at different experimental conditions.…”

Neuronal Sirt1 Deficiency Increases Insulin Sensitivity in Both Brain and Peripheral Tissues

“…Interestingly, the deletion of exon4 in SINKO hypothalamus has not only resulted in a molecular weight shift of the mutant protein, but also caused a reduction of total Sirt1 protein content (Fig. 1C), a phenomenon that has been reported previously in other Sirt1 KO models (13)(14)(15). To further provide evidence for the magnitude of the Sirt1 deacetylase deletion, we found a marked increase in acetylation of the well-known Sirt1 targets p53 and Stat3 in hypothalamic extracts of SINKO mice (Fig.…”

Deleted in Breast Cancer 1 (DBC1) Protein Regulates Hepatic Gluconeogenesis

“…However, we have shown previously that the interaction between DBC1 and SIRT1 is disrupted under fasting conditions (19) and that the kinases AMP-activated protein kinase (AMPK) and PKA regulate the interaction between both proteins (20). SIRT1, a NADdependent deacetylase, regulates glucose metabolism in the liver through deacetylation of several targets, although different models provide conflicting results (21)(22)(23)(24)(25)(26)(27)). It appears that SIRT1 deacetylates PGC1␣ (21) and FOXO (Forkhead box) (28), increasing their transcriptional activity.…”