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. 2022 Apr 20;10(5):1883–1893. doi: 10.1016/j.gendis.2022.03.019

Figure 1.

Fig. 1

Schematic overview of the roles of NNMT in liver diseases. NNMT consumes the universal methyl donor SAM to methylate NAM, by which reaction NNMT directly links the methionine cycle with the methylation balance and NAD+ salvage pathway. SAM decreases caused by NNMT activity can change methylation levels of histone, non-histone protein, and DNA, which link to liver diseases, such as HCC, and liver fibrosis/cirrhosis. NNMT regulates the expression and activity of Sirt3 by changing NAD+ content. Sirt3 is associated with fatty acid oxidative. In addition, MNAM, the product of NNMT, interferes with Sirt1 degradation, leading to deacetylation of Sirt1 targets and suppression of lipid and cholesterol synthesis in hepatocytes. Both Sirt1 and Sirt3, participate in the developing process of NAFLD and ALD. MNAM is also related to hepatitis via the prostacyclin (PGI2)-dependent signaling. MNAM can be further oxidized by Aox into two related compounds, 2PY and 4PY, redundant MNAM and its metabolites are eventually excreted in the urine.