Source of nicotinamide governs its metabolic fate in cultured cells, mice, and humans

Abstract

Metabolic routing of nicotinamide (NAM) to NAD + or 1-methylnicotinamide (MeNAM) has impacts on human health and aging. NAM is imported by cells or liberated from NAD + . The fate of 2 H 4 -NAM in cultured cells, mice, and humans was determined by stable isotope tracing. 2 H 4 -NAM is an NAD + precursor via the salvage pathway in cultured A549 cells and human PBMCs and in A549 cell xenografts and PBMCs from 2 H 4 -NAM-dosed mice and humans, respectively. 2 H 4 -NAM is a MeNAM precursor in A549 cell cultures and xenografts, but not isolated PBMCs. NAM released from NAD + is a poor MeNAM precursor. Additional A549 cell tracer studies yielded further mechanistic insight. NAMPT activators promote NAD + synthesis and consumption. Surprisingly, NAM liberated from NAD + in NAMPT activator-treated A549 cells is also routed toward MeNAM production. Metabolic fate mapping of the dual NAM sources across the translational spectrum (cells, mice, humans) illuminates a key regulatory node governing NAD + and MeNAM synthesis.