NF-Y Involvement in the Polyunsaturated Fat Inhibition of Fatty Acid Synthase Gene Transcription

Abstract

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 PUFA 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 PUFA suppression of FAS promoter activity. In addition, extended cloning and transfection-reporter assays revealed that the FAS gene contains a second PUFA response region (PUFA-RR) in the distal area of −7382/−6970. Interestingly, the distal PUFA-RR FAS has many similarities to the PUFA-RR of l-pyruvate kinase gene while the proximal PUFA-RR FAS is comparable to the PUFA-RR of the S14 and stearoyl-CoA desaturase genes.