In NASH, steatosis is frequently regarded as the first “hit” and is hypothesized to be the prerequisite for progression to steatohepatitis. A second, not yet definitively identified, “hit” is required for the progression to steatohepatitis. This second hit has been proposed to include cellular processes such as mitochondrial injury, oxidative stress, innate immunity or proinflammatory cytokines. The phosphatase and tensin homolog deleted on chromosome Akt pathway is well documented in its ability to directly regulate de novo lipogenesis in the liver. PTEN is a dual specificity phosphatase possessing both lipid and protein phosphatase activity and is a member of the protein tyrosine phosphatase family of phosphatases. PTEN negatively regulates Akt activation through its ability to dephosphorylate the 3-position phosphate from PtdIns P3 to produce PtdIns P2. Inactivation of PTEN leads to sustained Akt activation in both cellular and animal models. Hepatospecific deletion of PTEN is an established model to examine the effects of a NASH-like condition. In the liver, PTENf/f results in insulin hypersensitivity, hepatomegaly, triglycerides, and constitutive activation of DNL. As these mice age, a progression into steatohepatitis and ultimately hepatocellular carcinoma occurs in mice fed normal chow diets. PTEN expression in other organs and tissues is normal but there is an overall reduction in overall body fat. In the present study, the effects of short term feeding of a HFD was used as a second hit and examined in a background of enhanced steatosis that occurs in PTENf/f mice. We demonstrate that addition of a HFD significantly exacerbates hepatocellular damage and oxidative stress in PTENf/f mice. Furthermore, HFD suppresses expression of de novo synthetic enzymes downstream of Akt and upstream of SREBP1. This study also provides additional insight into the mechanism of HFD-induced oxidative stress and delineates the relative contribution of the PTEN/Akt pathway in HFD-induced hepatocellular damage. The accumulation of fat is the first step in the progression of NASH. In this study, it by the addition of a second hit in the form of a HFD over a short time course. Not surprisingly, in our Alb-Cre animals, the addition short term HFD only induced a mild accumulation of hepatic triglycerides and only demonstrated a trend in increased hepatocellular damage. This is an expected result, a longer duration of feeding is necessary to produce hepatocellular damage in normal mice. In the Alb-Cre model, HFD promoted alterations in cellular REDOX homeostasis as evidenced by decreased GST activity, increased GPx activity and decreased GSSG concentrations. This is in agreement with other studies where HFD was fed for longer periods of time. When we examined individual isoforms of GST we did not detect significant differences in expression following HFD in the Alb-Cre groups.