Nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease, is characterized by hepatic steatosis and hepatocellular injury and progresses to cirrhosis and hepatocellular carcinoma. Sterol regulatory element-binding proteins (SREBPs) are master regulators of lipogenesis. Liver-specific PTEN knockout (KO) mice show constitutive upregulation of SREBP through PI3K-Akt pathway activation, leading to spontaneous fatty liver and subsequent HCC development. SREBP cleavage-activating protein (SCAP) plays a critical role in SREBP activation. We sought to determine the impact of SREBP inhibition on NASH and HCC development. To this end, we additionally inhibited SREBP pathway in liver-specific PTEN mice by ablating SCAP and generated liver-specific PTEN/SCAP double KO (DKO) mice. However unexpectedly, inhibition of SCAP/SREBP pathway markedly exacerbated liver injury (5weeks), fibrosis (5months), and carcinogenesis (7 months) in PTEN KO mice. To elucidate the mechanisms of liver injury in liver-specific PTEN/SCAP DKO mice, we conducted transcriptome analyses of the livers. Overall design: PTEN F/F, SCAP F/F and PTEN/SCAP F/F mice were crossed to Alb-Cre mice to generate liver-specific PTEN KO, SCAP KO and PTEN/SCAP DKO mice, respectively. Wilt type, liver-specific PTEN KO, SCAP KO and PTEN/SCAP DKO mice were fed with normal diet for 5 weeks, and total RNA samples were extracted from liver tissues. We compared relative liver gene expression levels across these mice.