Nicotinamide N-methyltransferase expression decreases in iron overload, exacerbating toxicity in mouse hepatocytes.

Iron overload causes the generation of reactive oxygen species that can lead to lasting damage to the liver and other organs. The goal of this study was to identify genes that modify the toxicity of iron overload. We studied the effect of iron overload on the hepatic transcriptional and metabolomic profile in mouse models using a dietary model of iron overload and a genetic model, the hemojuvelin knockout mouse. We then evaluated the correlation of expression with body iron stores in human patients and the effect of knockdown on gene expression and viability in primary mouse hepatocytes. We found that iron overload induced significant changes in the expression of genes and metabolites involved in glucose and nicotinamide metabolism and that , an enzyme that methylates nicotinamide and regulates hepatic glucose and cholesterol metabolism, is one of the most strongly down-regulated genes in the liver in both genetic and dietary iron overload. We found that hepatic expression is inversely correlated with serum ferritin levels and serum transferrin saturation in patients who are obese, suggesting that body iron stores regulate human liver expression. Furthermore, we demonstrated that adenoviral knockdown of in primary mouse hepatocytes exacerbates iron-induced hepatocyte toxicity and increases expression of transcriptional markers of oxidative and endoplasmic reticulum stress, while overexpression of partially reversed these effects. : Iron overload alters glucose and nicotinamide transcriptional and metabolic pathways in mouse hepatocytes and decreases expression, while deficiency worsens the toxic effect of iron overload. For these reasons, may be a drug target for the prevention of iron-induced hepatotoxicity. ( 2017;1:803-815).