ABSTRACT: Social stress is well known to be involved in the occurrence and exacerbation of mental illness, and also various life-style related diseases such as hyperinsulinemia, hyperglycemia, cardiovascular diseases and cancer. However, there is little information on tissue-specific gene expression in response to social stress, which reflects our daily life. Liver is one of the most important organs, owing to its biological functions such as energy metabolic homeostasis, metabolization and detoxification of endo- and exogenous substances. In order to elucidate the mechanism underlying response to social stress in the liver, we investigated hepatic gene expression in mice exposed to isolation stress using DNA microarray. Male BALB/c mice (4 weeks old) were housed 5 per cage for 10 days acclimatization. Then mice were exposed to isolation stress for 30 days. After stress treatment, the mouse liver RNA was subjected to DNA microarray analysis. Taking the false discovery rate into account, isolation stress altered expression of 420 genes. Moreover, Gene Ontology analysis of these differentially expressed genes indicated that isolation stress remarkably down-regulated lipid metabolism-related pathway through peroxisome proliferator-activated receptor-ï¡ (PPARï¡), while lipid biosynthesis pathway regulated by sterol regulatory element binding factor-1 (SREBF-1), Golgi vesicle transport and secretory pathway-related genes were significantly up-regulated. These results suggested that isolation for 30 days, mild and consecutive social stress, not only regulate the systems for lipid metabolism but also cause the endoplasmic reticulum stress in mouse liver. Experiment Overall Design: Male BALB/c mice (4 weeks old, Japan SLC, Shizuoka, Japan) weighing 14-18 g were housed 5 per cage. After acclimatization for 10 days, the mice were exposed to isolation (1 mouse per cage). All cages were placed in a foam plastic box in order to avoid social contact. To enhance the feeling of isolation, the bed volume in each cage for the isolated mice was reduced to one-tenth of that in the control group. The weight of bedding chips was about 2 g. All mice were housed in an air-conditioned room ( room temperature: 23 ± 1°C, humidity: 55 ± 5 %) under 12 h dark/12 h light cycles, with free access to tap water and MF diet (Oriental Yeast Co., Tokyo, Japan).