title: Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome.
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.
authors.affiliation: Department of Anesthesiology and Kogod Aging Center, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Escande
authors.forename: Veronica
authors.initials: V
authors.lastname: Nin
authors.forename: Nathan L
authors.initials: NL
authors.lastname: Price
authors.forename: Verena
authors.initials: V
authors.lastname: Capellini
authors.forename: Ana P
authors.initials: AP
authors.lastname: Gomes
authors.forename: Maria Thereza
authors.initials: MT
authors.lastname: Barbosa
authors.forename: Luke
authors.initials: L
authors.lastname: O'Neil
authors.forename: Thomas A
authors.initials: TA
authors.lastname: White
authors.forename: David A
authors.initials: DA
authors.lastname: Sinclair
authors.forename: Eduardo N
authors.initials: EN
authors.lastname: Chini
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D047310:Apigenin / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D024821:Metabolic Syndrome / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015394:Molecular Structure; D009243:NAD / Q000378:metabolism*; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D011794:Quercetin / Q000737:chemistry / Q000494:pharmacology; D011897:Random Allocation; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D009243:NAD; D047310:Apigenin; D011794:Quercetin; D051997:ADP-ribosyl Cyclase 1; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1