Flavonoid Apigenin Is an Inhibitor of the NAD+ase CD38

Abstract

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.

Luteolinidin Protects the Postischemic Heart through CD38 Inhibition with Preservation of NAD(P)(H)

“…With Lineweaver-Burk analysis, we found that CD38 noncompetitively inhibits CD38 with decreasing V max and unchanging K m with increasing inhibitor concentration. This is in contrast with prior studies that identified luteolinidin as a competitive inhibitor of CD38 (Kellenberger et al, 2011;Escande et al, 2013). Consistent with noncompetitive inhibition, the decreasing V max cannot be overcome by increasing substrate concentration, unlike with competitive inhibition (Michaelis et al, 2011).…”

“…Flavonoid anthocyanidin compounds were recently shown to inhibit CD38 with relatively high potency compared with previously used inhibitors, with luteolinidin found to be the most potent of the flavonoids tested (Kellenberger et al, 2011;Escande et al, 2013). Anthocyanidins, such as luteolinidin, are a subgroup of the broad family of flavonoids, which has thousands of known compounds (Nijveldt et al, 2001) (Fig.…”

Apigenin Causes Biochemical Modulation, Glut4 and Cd38 Alterations to Improve Diabetes and to Protect Damages of Some Vital Organs in Experimental Diabetes

“…Our findings provide mechanistic evidence that apigenin downregulates CD38 expression in type II diabetic rats. This data is consistent with the apigenin-mediated improvement of glucose homeostasis via SIRT1 activation and promotion of fatty acid oxidation along with reduction of lipids accumulation (Escanade et al, 2013). Importantly, our study reveals that pharmacological downregulation or inhibition of CD38 expression at the molecular level can be a therapeutic approach to treat T2D.…”

“…CD38 enzyme is a NAD + ase which degrades NAD + in tissue and promotes metabolic syndrome (Escanade et al, 2013). Our findings provide mechanistic evidence that apigenin downregulates CD38 expression in type II diabetic rats.…”

“…Reduction in insulin-mediated glucose uptake caused by decreasing GLUT4 protein translocation in Type 2 Diabetes (T2D) has been observed (Olson et al, 2012). Cluster of Differentiation 38 (CD38) enzyme degrades NAD + in tissue and promotes T2D and other metabolic syndrome (Escanade et al, 2013). Thus, facilitation of GLUT4 translocation by modulation of insulin signaling pathway and inhibition of CD38 protein can be potential therapeutic target for the treatment of T2D.…”