Our Major Research Interests
Vitamin B3 (nicotinamide and nicotinic acid) is the precursor for NAD(P), one of the central compounds of intermediary metabolism and a cofactor for more than 200 enzymes. In addition, NAD also serves as a co-substrate for a number of enzymes such as sirtuins, poly- and mono-ADP ribosyltransferases and ADP-ribosyl cyclases (CD38, CD157). Recent resurgence in the study nicotinamide/NAD metabolism is the result of the realization that sirtuins and especially Sirt1, a putative mediator of the beneficial effects of caloric restriction, is a NAD dependent deacetylase. Sirt1 activity is regulated by the availability of its substrate NAD and inhibited by the precursor nicotinamide.
Vitamin B3 cannot be stored and excess must be secreted. Excess intake has been linked to liver failure. Two enzymatic systems have been described that clear nicotinamide from the liver. The first is methylation of nicotinamide by the enzyme nicotinamide N-methyltransferase (NNMT). The product, N1-methynicotinamide can be further oxidized to two related compounds, 2- and 4-pyridone carboxamides, by aldehyde oxidase, and all three are ultimately excreted in the urine. The second is a microsomal oxidation pathway of nicotinamide to nicotinamide N-oxide by an unknown enzyme (likely to be a p450 containing system).
We are pursuing the hypothesis, that nicotinamide clearance pathways are involved in the regulation of glucose and lipid metabolism though Sirt1-dependent and independent mechanisms and might be potential new targets for metabolic disease therapy. To this end, our laboratory uses a combination of biochemical and physiological approaches that include HPLC measurements of the relevant metabolites, in vitro systems such as standard cell culture, mouse primary hepatocytes and 3T3-L1 cells and mouse models of metabolic disease. We are using adenoviral and lentiviral vectors to selectively knockdown and overexpress the relevant enzymes and are further developing in vivo models to elucidate the role of nicotinamide clearance in diabetes, obesity and liver disease.
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