Regulation of Nampt expression by transcriptional coactivator NCOA6 in pancreatic β-cells

Nuclear receptor coactivator 6 (NCOA6) is a transcriptional coactivator and crucial for insulin secretion and glucose metabolism in pancreatic β-cells. However, the regulatory mechanism of β-cell function by NCOA6 is largely unknown. In this study, we found that the transcript levels of nicotinamide phosphoribosyltransferase (Nampt) were decreased in islets of NCOA6+/− mice compared with NCOA6+/+ mice. Moreover, NCOA6 overexpression increased the levels of Nampt transcripts in the mouse pancreatic β-cell line NIT-1. Promoter analyses showed that transcriptional activity of the Nampt promoter was stimulated by cooperation of sterol regulatory element binding protein-1c (SREBP-1c) and NCOA6. Additional studies using mutant promoters demonstrated that SREBP-1c activates Nampt promoter through the sterol regulatory element (SRE), but not through the E-box. Using chromatin immunoprecipitation assay, NCOA6 was also shown to be directly recruited to the SRE region of the Nampt promoter. Furthermore, treatment with nicotinamide mononucleotide (NMN), a product of the Nampt reaction and a key NAD+ intermediate, ameliorates glucose-stimulated insulin secretion from NCOA6+/− islets. These results suggest that NCOA6 stimulates insulin secretion, at least partially, by modulating Nampt expression in pancreatic β-cells. [Display omitted] •Nampt transcription in β-cells is activated by SREBP-1c through the SRE element.•NCOA6 enhances the transcriptional activity of SREBP-1c in the Nampt promoter.•Defective insulin secretion of NCOA6+/− islets is recovered by NMN treatment.•NCOA6 is reportedly the first coactivator involved in Nampt expression.