Dietary polyunsaturated fats (PUFA) reduce the hepatic content of SREBP-1 65-75%, and this is paralleled by a comparable decrease in the expression of fatty acid synthase (FAS) gene. The close association between the nuclear content of SREBP-1 and FAS transcription has led to the conclusion that PUFA inhibit lipogenic gene transcription by suppressing SREBP-1 expression, but this conclusion is based upon correlative data. When in fact the SREBP-1/USF sites of the insulin response element of FAS were mutated, only 25% of the PLTFA inhibition of FAS promoter activity was lost. On the other hand, mutating the -99/ -93 NF-Y site reduced overall promoter activity 85%, and eliminated 50% of the PLTFA suppression of FAS promoter activity. In addition, extended cloning and transfection-reporter assays revealed that the FAS gene contains a second PLTFA response region (PUFA. RR) in the distal area of -7382/-6970. Interestingly, the distal PUFA-RRFAS has many similarities to the PUFA-RR of L-pyruvate kinase gene while the proximal PUFA-RRFAS is comparable to the PUFA-RR of the S14 and stearoyl-CoA desaturase genes. (C) 2002 Elsevier Science (USA).