Flavonoid Apigenin Is an Inhibitor of the NAD+ase CD38: Implications for Cellular NAD+ Metabolism, Protein Acetylation, and Treatment of Metabolic Syndrome
Price, Nathan L.
Gomes, Ana P.
Barbosa, Maria Thereza
White, Thomas A.
Chini, Eduardo N.
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CitationEscande, Carlos, Veronica Nin, Nathan L. Price, Verena Capellini, Ana P. Gomes, Maria Thereza Barbosa, Luke O’Neil, Thomas A. White, David A. Sinclair, and Eduardo N. Chini. 2013. “Flavonoid Apigenin Is an Inhibitor of the NAD+ase CD38: Implications for Cellular NAD+ Metabolism, Protein Acetylation, and Treatment of Metabolic Syndrome.” Diabetes 62 (4): 1084-1093. doi:10.2337/db12-1139. http://dx.doi.org/10.2337/db12-1139.
AbstractMetabolic 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.
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