NNMT is highly expressed in the human liver.[6][7] N-methylation is one method by which drug and other xenobiotic compounds are metabolized by the liver.[6] NNMT expression in adipose tissue is associated with obesity and insulin resistance.[6][8] Contrary to the negative effects of increased NNMT in adipose tissue, increased NNMT in liver is associated with a better metabolic profile, namely reduced serum triglycerides and free fatty acids.[8] In adipose tissue, NNMT can lead to methylation depletion, whereas because of the many methylation enzymes in the liver NNMT has a negligible effect on liver methylation.[6] But in the liver, the 1-methylnicotinamide produced by NNMT degradation of nicotinamide increases sirtuin 1 (SIRT1) by inhibiting degradation of that protein.[8] Overexpression of SIRT1 in mice has been shown to reduce insulin and fasting glucose, as well as increased metabolism and physical function.[9]
Abundant availability of nicotinamide leads to depletion of both nicotinamide adenine dinucleotide (NAD+) and SAM-e, resulting in liver steatosis and fibrosis, causing the progression from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH).[10]
Human embryonic stem cells expression of NNMT is believed to help maintain the cells in a naive state.[6]
NNMT expression is significantly upregulated in many cancers, including pancreatic cancer where levels of NNMT enzyme correlate with increased risk of death.[11] The cause of these correlations has not been established, but may be related to the fact that NNMT enzyme is an inhibitor of DNA repair.[11] NNMT and 1-methylnicotinamide inhibit autophagy in breast cancer, protecting breast cancer cells against oxidative stress.[12] NNMT has been suggested to be a biomarker of cancer.[11]
