type (WT) mice fed with HFD, (ii) examining the effects of 18-carbon FA [stearic acid (SA, C18:0), oleic acid (OA, C18:1), linoleic acid (LA, C18:2), and alpha-linolenic acid (ALA, C18:3)], which significantly accumulated in the HFD fed mice liver, on Nrf2 and CYP2A6 expressions in HepG2 cells, and (iii) if the effects of 18-carbon FA on CYP2A5/2A6 expression are related to Nrf2 with Nrf2 silenced or over expressed HepG2 cells. As the classical target gene of Nrf2, GSTA1 mRNA expression was detected in Nrf2 silenced or over expressed HepG2 cells to indirectly reflect the activation of Nrf2. The results indicated that the HFD-induced hepatocellular 18-carbon FA accumulation up-regulates CYP2A5/2A6 via Nrf2 during hepatocytes steatosis. However, Nrf2 is not the only compound that regulates CYP2A5/2A6 expression.