Flavonoid Apigenin Is an Inhibitor of the NAD+ase CD38
Implications for Cellular NAD+ Metabolism, Protein Acetylation, and Treatment of Metabolic Syndrome
- Carlos Escande1,
- Veronica Nin1,
- Nathan L. Price2,
- Verena Capellini1,
- Ana P. Gomes2,
- Maria Thereza Barbosa1,
- Luke O’Neil1,
- Thomas A. White1,
- David A. Sinclair2 and
- Eduardo N. Chini1⇑
- 1Department of Anesthesiology and Kogod Aging Center Mayo Clinic, Rochester, Minnesota
- 2Glenn Laboratories for the Biological Mechanisms of Aging, Genetics Department, Harvard Medical School, Boston, Massachusetts.
- Corresponding author: Eduardo N. Chini, .
Metabolic syndrome is a growing health problem worldwide. It is therefore imperative to develop new strategies to treat this pathology. In the past years, the manipulation of NAD+ metabolism has emerged as a plausible strategy to ameliorate metabolic syndrome. In particular, an increase in cellular NAD+ levels has beneficial effects, likely because of the activation of sirtuins. Previously, we reported that CD38 is the primary NAD+ase in mammals. Moreover, CD38 knockout mice have higher NAD+ levels and are protected against obesity and metabolic syndrome. Here, we show that CD38 regulates global protein acetylation through changes in NAD+ levels and sirtuin activity. In addition, we characterize two CD38 inhibitors: quercetin and apigenin. We show that pharmacological inhibition of CD38 results in higher intracellular NAD+ levels and that treatment of cell cultures with apigenin decreases global acetylation as well as the acetylation of p53 and RelA-p65. Finally, apigenin administration to obese mice increases NAD+ levels, decreases global protein acetylation, and improves several aspects of glucose and lipid homeostasis. Our results show that CD38 is a novel pharmacological target to treat metabolic diseases via NAD+-dependent pathways.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-1139/-/DC1.
- Received August 22, 2012.
- Accepted October 9, 2012.
- © 2013 by the American Diabetes Association.
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