Seoul-t'ukpyolsi, Republic of Korea Here we investigated effects of anacardic acid (AA) on the regulation of lipogenesis in differentiated human adipocytes, and elucidated possible epigenetic mechanisms via p300 histone acetyltransferase activity. To investigate the role of histone acetylation in lipogenesis regulation, we evaluated triglyceride (TG) contents, expression of key lipogenic enzyme acetyl-CoA carboxylase (ACC) and sterol regulatory element binding protein 1c (SREBP-1c) in primary cultured adipocytes isolated from subcutaneous adipose tissues. Treatment of AA or knockdown of p300 by using transient transfection of p300 siRNA led to significant reduction of TG contents, SREBP-1c and ACC expression, indicating that p300 mediates SREBP-1, ACC expression, and corollary lipid production. While p300 overexpression by p300WT was associated with significantly enhanced activity of SREBP1-908luc promoter, the SREBP1-908luc promoter activity was significantly reduced in the presence of p300DHAT. In addition, we performed a promoter assay using HEK293T cells treated with AA or TSA. While the SREBP1-908luc promoter activity was significantly decreased by AA, but significantly increased by TSA treatment. These findings suggest that histone acetyltransferase activity of p300, not a p300 expression per se, is critical for the transcriptional regulation of SREBP-1 and p300HAT inhibitors such as AA could be employed as anti-obesity modalities.