Taken together, these studies demonstrate that there is an optimal range of SAMe and SAH concentrations in the liver that is maintained mainly by the concerted action of the enzymes MATI/III, GNMT, AHCY, CBS, BHMT, and MTHFR together with the adequate supply of labile methyl groups (methionine, choline, betaine, and serine) and that below and above this range of SAMe and SAH concentrations, fatty liver develops spontaneously, which can progress to NASH, fibrosis, and ultimately hepatocellular carcinoma. Here, MTHFR is linked to metabolic dysfunction-associated steatohepatitis.