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

Abstract

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 nicotinamide N‐methyltransferase (NNMT) expression with body iron stores in human patients and the effect of NNMT 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 NNMT, 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 NNMT 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 NNMT expression. Furthermore, we demonstrated that adenoviral knockdown of NNMT in primary mouse hepatocytes exacerbates iron‐induced hepatocyte toxicity and increases expression of transcriptional markers of oxidative and endoplasmic reticulum stress, while overexpression of NNMT partially reversed these effects. Conclusion: Iron overload alters glucose and nicotinamide transcriptional and metabolic pathways in mouse hepatocytes and decreases NNMT expression, while NNMT deficiency worsens the toxic effect of iron overload. For these reasons, NNMT may be a drug target for the prevention of iron‐induced hepatotoxicity. (Hepatology Communications 2017;1:803–815)

Atorvastatin and pravastatin stimulate nitric oxide and reactive oxygen species generation, affect mitochondrial network architecture and elevate nicotinamide N‐methyltransferase level in endothelial cells

“…Therefore, a putative role of NNMT as an important regulatory enzyme involved in a proper endothelial functioning has been considered, and it was a reasonable justification of our study. It was also found that an overexpression of NNMT reduces oxidative stress under various pathological conditions (Koppe et al, 2017;Xie et al, 2016). Postulated decrease in SAM concentration due to a stimulation of NNMT activity was expected to reduce protein methylation while less NAD + could limit protein F I G U R E 5 Effect of atorvastatin and pravastatin on AMPK, ACC phosphorylation, Sirtuin1, Sirtuin3 and NNMT.…”

Iron-Induced Hepatocarcinogenesis—Preventive Effects of Nutrients

“…Koppe, et al found that hepatic nicotinamide levels were significantly increased by a dietary iron challenge in mice (116). This was possibly due to iron-induced downregulation of nicotinamide N-methyltransferase (NNMT) in hepatocytes (116). Additionally, hepatic NNMT expression was negatively correlated with serum iron parameters in obese individuals (116).…”

“…Koppe, et al. found that hepatic nicotinamide levels were significantly increased by a dietary iron challenge in mice ( 116 ). This was possibly due to iron-induced downregulation of nicotinamide N -methyltransferase (NNMT) in hepatocytes ( 116 ).…”

“…This was possibly due to iron-induced downregulation of nicotinamide N -methyltransferase (NNMT) in hepatocytes ( 116 ). Additionally, hepatic NNMT expression was negatively correlated with serum iron parameters in obese individuals ( 116 ). Interestingly, NNMT knockdown exacerbated iron-induced damages while its overexpression protected hepatocytes from iron overload ( 116 ).…”

“…Additionally, hepatic NNMT expression was negatively correlated with serum iron parameters in obese individuals ( 116 ). Interestingly, NNMT knockdown exacerbated iron-induced damages while its overexpression protected hepatocytes from iron overload ( 116 ). NNMT stabilizes NAD + -dependent deacetylase SIRT1 by producing N 1 -methylnicotinamide ( 117 ).…”