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*
- From the Division of Nutritional Sciences and the Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712
Abstract
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. EC50 ∼10 μm), 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 PPARα-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.
Footnotes
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↵* This work was supported by National Institutes of Health Grants DK 52573 and DK 53872 (to S. D. C.) and DK 09723 (to M. T. N.) and by the sponsors of the M. M. Love Chair in Nutritional, Cellular and Molecular Sciences at the University of Texas at Austin (to S. D. C.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ To whom correspondence should be addressed: 115 Gearing, The University of Texas at Austin, Austin, TX 78712. Tel.: 512-232-1537; Fax: 512-471-5630; E-mail: stevedclarke@mail.utexas.edu.
- Abbreviations:
- PUFA
-
polyunsaturated fatty acids
- FAS
-
fatty acid synthase
- SREBP
-
sterol regulatory element binding protein
- PPAR
-
peroxisomal proliferator activated receptor
- Hepes
-
4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
- USF-1
-
upstream stimulatory factor-1
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- Received March 5, 1999.
- Revision received May 19, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
