The present study was performed to examine a hypothesis that peroxisome proliferator-activated receptor gamma (PPAR gamma) is implicated in high fat diet-induced liver steatosis. Mice were fed with control or high fat diet containing approximately 10% or 80% cholesterol, respectively. Macroscopic and microscopic findings demonstrated that lipid accumulation in the liver was observed as early as 2 weeks after high fat diet and that high fat diet for 12 weeks developed a fatty liver phenotype, establishing a novel model of diet-induced liver steatosis. Gene profiling with microarray and real-time PCR studies demonstrated that among genes involved in lipid metabolism, adipogenesis-related genes, PPAR gamma and its targeted gene, CD36 mRNA expression was specifically up-regulated in the liver by high fat diet for 2 weeks. Irnmunohistochemical study revealed that PPAR gamma protein expression is increased in the nuclei of hepatocytes by high fat diet. It was also shown that protein expression of cAMP response element-binding protein (CREB), an upstream molecule of PPAR gamma, in the liver was drastically suppressed by high fat diet. All these results suggest for the first time that the CREB-PPAR gamma signaling pathway may be involved in the high fat diet-induced liver steatosis. (c) 2005 Elsevier Inc. All rights reserved.