Sterol regulatory element binding protein-1 expression is suppressed by dietary polyunsaturated fatty acids. A mechanism for the coordinate suppression of lipogenic genes by polyunsaturated fats

• Published in: The Journal of biological chemistry 1999-08, Vol.274 (33), p.23577-23583
• Main Authors: Xu, J, Nakamura, T, Cho, H.P, Clarke, S.D
• Format: Article
• Language: English
• Subjects: CCAAT-Enhancer-Binding Proteins; Cell Line; cell lines; diet; Dietary Fats - pharmacology; DNA-Binding Proteins - genetics; Fatty Acids, Unsaturated - administration & dosage; Fatty Acids, Unsaturated - pharmacology; fatty-acid synthase; fish oils; gene expression; Gene Expression Regulation - drug effects; hepatocytes; Humans; liver; long chain fatty acids; messenger RNA; Nuclear Proteins - genetics; Peroxisome Proliferators - pharmacology; polyunsaturated fatty acids; Pyrimidines - pharmacology; rats; RNA, Messenger - genetics; RNA, Messenger - metabolism; safflower oil; Sterol Regulatory Element Binding Protein 1; transcription (genetics); Transcription Factors; triolein
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.274.33.23577

Polyunsaturated fatty acids (PUFA) coordinately suppress the transcription of a wide array of hepatic lipogenic genes including fatty acid synthase (FAS) and acetyl-CoA carboxylase. Interestingly, the over-expression of sterol regulatory element binding protein-1 (SREBP-1) induces the expression of all of the enzymes suppressed by PUFA. This observation led us to hypothesize that PUFA coordinately inhibit lipogenic gene transcription by suppressing the expression of SREBP-1. Our initial studies revealed that the SREBP-1 and FAS mRNA contents of HepG2 cells were reduced by 20:4(n-6) in a dose-dependent manner (i.e. EC(50) approximately 10 microM), whereas 18:1(n-9) had no effect. Similarly, supplementing a fat-free, high glucose diet with oils rich in (n-6) or (n-3) PUFA reduced the hepatic content of precursor and nuclear SREBP-1 60 and 85%, respectively; however, PUFA had no effect on the nuclear content of upstream stimulatory factor (USF)-1. The PUFA-dependent decrease in nuclear content of mature SREBP-1 was paralleled by a 70-90% suppression in FAS gene transcription. In contrast, dietary 18:1(n-9), i.e. triolein, had no inhibitory influence on the expression of SREBP-1 or FAS. The decrease in hepatic expression of SREBP-1 and FAS associated with PUFA ingestion was mimicked by supplementing the fat-free diet with the PPARalpha-activator, WY 14, 643. Interestingly, nuclear run-on assays revealed that changes in SREBP-1 mRNA abundance were not accompanied by changes in SREBP-1 gene transcription. These results support the concept that PUFA coordinately inhibit lipogenic gene transcription by suppressing the expression of SREBP-1 and that the PUFA regulation of SREBP-1 appears to occur at the post-transcriptional level.