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).
Excess vitamin B3 is secreted and pharmacological doses, as in niacin therapy have been linked to liver failure. Two enzymatic pathways 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 cyp2E1.
We are accumulating evidence that NNMT is not simply a clearance enzyme but is involved in the regulation of liver nutrient metabolism and might be a potential target for metabolic disease therapy.
Cyp2E1 is alcohol-induced member of the p450 family involved in the toxicity of several xenobiotics. We are pursuing the hypothesis, that ROS generation through this enzyme is one of the causes of nicotinamide toxicity.
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, 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 developing in vivo models to elucidate the role of nicotinamide clearance pathways in diabetes, obesity and liver disease.
For further inquires, please contact Pavlos Pissios.