Adding 2% cholesterol to the standard diet (10%E from fat) of P. obesus for 4 weeks caused these animals to develop non-alcoholic steatohepatitis (NASH). The animals exhibited hepatomegaly and impaired liver function with pronounced steatosis, and histopathological evidence of inflammation, cellular injury and fibrosis. The effect of adding cholesterol to the diet (without increasing dietary fat) was profound in P. obesus compared with other rodents, suggesting increased susceptibility to NASH in these animals. We profiled the hepatic expression of key genes involved in lipid metabolism in P. obesus fed either the standard or cholesterol-supplemented diet. Expression of genes involved in fatty acid/triglyceride synthesis were consistently decreased in the cholesterol-supplemented group (LFABP -48%, p=0.01; PPARa -59%, 0<0.001; GPAT -41%, p=0.02). PPARd gene expression was increased (+170%, p=0.007), presumably to increase transcription of genes involved in fatty acid oxidation, however CPT1 mRNA was decreased (-41%, p=0.03). Genes involved in lipid uptake were reduced (SREBP2 -37%, p=0.02; SRB1 -48%, p=0.002; LDLR -61%, p<0.001), while ABCA1 mRNA was increased (+230%, p=0.001), reflecting increased cholesterol efflux from the cells. Expression of 7 alpha hydroxylase, the rate-limiting step in bile acid synthesis, was reduced in livers of P. obesus fed the cholesterol-supplemented diet (-47%, p=0.02). The pattern of gene expression observed suggests down-regulation of lipogenesis, reduction in lipid uptake, and increased cholesterol efflux. All of these mechanisms would aim to reduce the toxic levels of lipids and cholesterol present in the cells. The reduction in 7 alpha hydroxylase mRNA is consistent with results previously found in rabbits and African green monkeys, and is a mechanism to reduce bile acid synthesis, thus reducing further uptake of dietary lipids and cholesterol. P. obesus are highly susceptible to the development of NASH, and represent a new model in which to investigate the mechanisms involved in the etiology and progression of this disease.