SS and DK contributed equally to this study.
Elevated microRNA-34a in obesity reduces NAD+ levels and SIRT1 activity by directly targeting NAMPT
Article first published online: 11 AUG 2013
© 2013 the Anatomical Society and John Wiley & Sons Ltd
Volume 12, Issue 6, pages 1062–1072, December 2013
How to Cite
Choi, S.-E., Fu, T., Seok, S., Kim, D.-H., Yu, E., Lee, K.-W., Kang, Y., Li, X., Kemper, B. and Kemper, J. K. (2013), Elevated microRNA-34a in obesity reduces NAD+ levels and SIRT1 activity by directly targeting NAMPT. Aging Cell, 12: 1062–1072. doi: 10.1111/acel.12135
- Issue published online: 21 NOV 2013
- Article first published online: 11 AUG 2013
- Accepted manuscript online: 8 JUL 2013 05:38AM EST
- Manuscript Accepted: 27 JUN 2013
- Korean Health 21 R&D Project, Ministry of Health and Welfare. Grant Number: A102065
- MRC. Grant Number: 2012–051426
- National Institutes of Health. Grant Number: DK62777 and DK95842
SIRT1 is an NAD+-dependent deacetylase that is implicated in prevention of many age-related diseases including metabolic disorders. As SIRT1 deacetylase activity is dependent on NAD+ levels and the development of compounds that directly activate SIRT1 has been controversial, indirectly activating SIRT1 through enhancing NAD+ bioavailability has received increasing attention. NAD+ levels are reduced in obesity and the aged, but the underlying mechanisms remain unclear. We recently showed that hepatic microRNA-34a (miR-34a), which is elevated in obesity, directly targets and decreases SIRT1 expression. Here, we further show that miR-34a reduces NAD+ levels and SIRT1 activity by targeting NAMPT, the rate-limiting enzyme for NAD+ biosynthesis. A functional binding site for miR-34a is present in the 3′ UTR of NAMPT mRNA. Hepatic overexpression of miR-34a reduced NAMPT/NAD+ levels, increased acetylation of the SIRT1 target transcriptional regulators, PGC-1α, SREBP-1c, FXR, and NF-κB, and resulted in obesity-mimetic outcomes. The decreased NAMPT/NAD+ levels were independent of miR-34a effects on SIRT1 levels as they were also observed in SIRT1 liver-specific knockout mice. Further, the miR-34a-mediated decreases were reversed by treatment with the NAD+ intermediate, nicotinamide mononucleotide. Conversely, antagonism of miR-34a in diet-induced obese mice restored NAMPT/NAD+ levels and alleviated steatosis, inflammation, and glucose intolerance. Anti-miR-34a-mediated increases in NAD+ levels were attenuated when NAMPT was downregulated. Our findings reveal a novel function of miR-34a in reducing both SIRT1 expression and activity in obesity. The miR-34a/NAMPT axis presents a potential target for treating obesity- and aging-related diseases involving SIRT1 dysfunction like steatosis and type 2 diabetes.