Leptin-deficient ob/ob mice show many characteristics of obesity, including excess peripheral adiposity as well as severe hepatic steatosis, at least in part, due to increased hepatic lipogenesis. Polyunsaturated fatty acids (PUFAs) are not only ligands for peroxisome proliferator-activated receptor (PPAR) ␣ but are also negative regulators of hepatic lipogenesis, which is thought to be mediated by the repression of sterol regulatory element-binding protein ( S terol regulatory element-binding proteins (SREBPs) are members of the basic helix-loop-helix leucine zipper family of transcription factors that regulate fatty acid and cholesterol synthesis (reviewed in Brown and Goldstein 1 ). Unlike other members of the family, SREBPs are synthesized as precursors bound to the endoplasmic reticulum and nuclear envelope and are released from the membrane into the nucleus as mature proteins by cleavage processes. To date, 3 isoforms of SREBP, -1a, -1c, and -2, have been identified and characterized. The predominant SREBP-1 isoform in liver and adipose tissue is SREBP-1c. Whereas SREBP-2 plays a crucial role in regulation of cholesterol synthesis, SREBP-1c controls the transcription and expression of lipogenic enzymes such as fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1) (reviewed in Shimano 2 and Horton et al. 3 ). It is remarkable that SREBP-1c regulates not only the synthetic rate of triglycerides but also the amount of their storage in the liver. 4,5 Thus, SREBP-1 has been revealed to be a promising target for hepatic steatosis (fatty livers) from a therapeutic point of view.The leptin-deficient ob/ob mouse model of obesity exhibits severe obesity and obesity-related symptoms, including hepatic steatosis and insulin resistance (reviewed in Bray and York 6 ). The livers of ob/ob mice have an increase in triglyceride content, probably because of the increased lipogenesis paralleled by elevated messenger RNA (mRNA) expression and enzymatic activity of several lipogenic enzymes such as FAS and SCD1. 6,7 Recently, it has been reported that both SREBP-1c mRNA and its active nuclear protein are increased in ob/ob mouse livers. 8 Furthermore, we have demonstrated in a previous report 5 that the disruption of the SREBP-1 gene in ob/ob mice leads to marked amelioration of hepatic steatosis.Dietary polyunsaturated fatty acids (PUFAs) of the n-6 and n-3 families are well established as negative regulators of hepatic lipogenesis (reviewed in Clark and Jump 9 ). Recently, others and we have shown that the suppressive