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Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease worldwide in association with oxidative stress and insulin resistance. Steatosis can evolve to steatohepatitis (NASH) by lipotoxicity, inflammation, fibrosis and cell death leading to cirrhosis and hepatocellular carcinoma. No valid therapy has been developed so far to control inflammatory and fibrogenic pathways of NAFLD/NASH. α-Tocopherol (α-TOH) is an antioxidant that partially reverts the histopatological spectrum of NASH. However, the biological mechanism that may support a preventive or therapeutic role of vitamin E in NASH and chronic liver diseases remain elusive. In this study we explored in vitro and in vivo the metabolism of vitamin E in liver cells and in the whole liver exposed to some pathogenic stimuli associated with the progression of NAFLD/NASH. Protein levels of CYP4F2, the cytochrome P450 isoenzyme involved in the metabolism of vitamin E increased in HepG2 cells incubated with α-TOH. This effect increased with a synergic action by the treatment with the fatty acids oleic acid or palmitic acid, or with fructose, which are well-known NASH stimuli. In mice fed control or NAFLD/NASH diets, e.g. high-fat (HFD) or HFD plus fructose diet, the abnormal lipid metabolism of liver tissue was associated with a lowered expression of CYP4F2 protein. The same finding was observed in animals treated with CCl4, a free radical-generating hepatotoxic xenobiotic leading to hepatic fibrosis, in the presence of lowered levels of liver α-TOH. In conclusion, either acute or chronic challenges with NAFLD/NASH stimuli influence the liver expression of CYP4F2. The observed acute transcriptional upregulation and the in vivo downregulation of this protein, point to a role for CYP4F2 in the inflammatory and lipotoxicity signaling of NASH. Transcriptional effects of vitamin E on this gene may help to explain earlier and positive clinical findings, which are worth of further investigation.