Introduction and Objective: β cell dysfunction is the driving force of type 2 diabetes mellitus (T2DM) pathogenesis. SIRT7 is an NAD+-dependent lysine deacetylase with diverse functions in glucose metabolism. However, its role in islet remains uncharacterized. Here, we explored the functional role of SIRT7 in β cell physiology and pathophysiology.Methods: We generated Sirt7 β cell specific knockout (Sirt7 βKO) mice and Sirt7-/- INS1 cells to determined the in vitro and in vivo phenotype of SIRT7 in healthy and dysfunctional β cells. Co-immunoprecipitation mass spectrometry was performed for SIRT7 interactome. RNA-seq, ChIP-seq and CUT&RUN are used to determine SIRT7 targets and the epigenetic mechanisms in β cells.Results: We observed reduced glucose tolerance in Sirt7 βKO mice and GSIS in isolated SIRT7-/- islets. Loss of Sirt7 in islets results in the decrease of insulin content, and insulin secretion capacity, and reduced expression of insulin secretion genes such as Ins1. The glucose intolerance of SIRT7 βKO mice and reduced GSIS function in SIRT7-/- islets is exacerbated by high fat diet or inflammatory cytokines. In contrast to other sirtuin members, SIRT7 only targets a very selective histone marks, such H3K18ac. Interestingly, we found that H3K18ac is highly induced by inflammation in β cells, whereas SIRT7 represses H3K18Ac at the enhancers related to inflammation. SIRT7 interacts with vitamin D receptor (VDR), a key modulator of inflammation and β cell survival. We showed that the protective effect of VDR on cytokine stressed depends on SIRT7. Lastly, boosting NAD+ is known to enhance β cell function. Our data showed that this protective effect is partially mediated through the VDR-SIRT7 axis.Conclusion: This study demonstrates that vitamin D and NAD+, both beneficial for β cell function, converge through VDR-SIRT7 to orchestrate the epigenome of β cells in homeostasis and stress.
J. Wu: None. L. Wang: None. X. Sun: None. Z. Wei: None.
NIH (K01DK120808, R01DK132651, UL1TR002377)
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