Sterol Regulatory Element Binding Protein-1 Expression Is Suppressed by Dietary Polyunsaturated Fatty Acids
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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.
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n-3 PUFAs suppress de novo lipogenesis by inhibiting SREBP-1 expression and maturation and reducing ChREBP activity, thereby curbing hepatic glycolysis and lipid synthesis.
“Beyond enhancing β-oxidation, n-3 PUFAs concurrently suppress de novo lipogenesis by inhibiting the expression and maturation of SREBP-1, and by reducing the activity of ChREBP, thereby curbing hepatic glycolysis and lipid synthesis.34–37”
Cites
Kliewer, S. A., Sundseth, S. S., Jones, S. A., Brown, P. J., Wisely, G. B., Koble, C. S., Devchand, P., Wahli, W., Willson, T. M., Lenhard, J. M., et al. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.9.4318 · Cited by 2,164 · see citing works
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SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215593 · Cited by 4,092 · see citing works
The Opposing Effects of N-3 and n-6 Fatty Acids
Schmitz, G., & Ecker, J. (2008) · Progress in Lipid Research · doi:10.1016/j.plipres.2007.12.004 · Cited by 1,245 · see citing works
Defining high-fat-diet rat models: Metabolic and molecular effects of different fat types
Buettner, R., Parhofer, K. G., Woenckhaus, M., Wrede, C. E., Kunz-Schughart, L. A., Schölmerich, J., & Bollheimer, L. C. (2006) · Journal of Molecular Endocrinology · doi:10.1677/jme.1.01909 · Cited by 704 · see citing works
Mechanisms of nutritional and hormonal regulation of lipogenesis
Kersten, S. (2001) · The EMBO Reports · doi:10.1093/embo-reports/kve071 · Cited by 700 · see citing works
Unsaturated Fatty Acids Down-regulate SREBP Isoforms 1a and 1c by Two Mechanisms in HEK-293 Cells
Hannah, V. C., Ou, J., Luong, A., Goldstein, J. L., & Brown, M. S. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m007273200 · Cited by 448 · see citing works
Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression
Sekiya, M., Yahagi, N., Matsuzaka, T., Najima, Y., Nakakuki, M., Nagai, R., Ishibashi, S., Osuga, J.-I., Yamada, N., & Shimano, H. (2003) · Hepatology · doi:10.1016/j.hep.2003.09.028 · Cited by 415 · see citing works
Kabir, M., Catalano, K. J., Ananthnarayan, S., Kim, S. P., Van Citters, G. W., Dea, M. K., & Bergman, R. N. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00203.2004 · Cited by 327 · see citing works
Dentin, R. (2005) · Journal of Clinical Investigation · doi:10.1172/jci25256 · Cited by 315 · see citing works
Koo, H.-Y., Wallig, M. A., Chung, B. H., Nara, T. Y., Cho, B. H. S., & Nakamura, M. T. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2008.02.007 · Cited by 164 · see citing works
Self-citationBotolin, D., Wang, Y., Christian, B., & Jump, D. B. (2006) · Journal of Lipid Research · doi:10.1194/jlr.m500365-jlr200 · Cited by 162 · see citing works
Buckley, R., Shewring, B., Turner, R., Yaqoob, P., & Minihane, A. M. (2004) · British Journal of Nutrition · doi:10.1079/bjn20041235 · Cited by 118 · see citing works
Teran-Garcia, M., Adamson, A. W., Yu, G., Rufo, C., Suchankova, G., Dreesen, T. D., Tekle, M., Clarke, S. D., & Gettys, T. W. (2007) · Biochemical Journal · doi:10.1042/bj20061722 · Cited by 104 · see citing works
Self-citationLDL cholesterol-raising effect of low-dose docosahexaenoic acid in middle-aged men and women.
Theobald, H. E., Chowienczyk, P. J., Whittall, R., Humphries, S. E., & Sanders, T. A. (2004) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/79.4.558 · Cited by 101 · see citing works
Hepatic deletion of Mboat7 (LPIAT1) causes activation of SREBP-1c and fatty liver
Xia, M., Chandrasekaran, P., Rong, S., Fu, X., & Mitsche, M. A. (2021) · Journal of Lipid Research · doi:10.1194/jlr.ra120000856 · Cited by 60 · see citing works
Pourrajab, B., Sharifi-Zahabi, E., Soltani, S., Shahinfar, H., & Shidfar, F. (2023) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2022.2100314 · Cited by 15 · see citing works
Li, L., Cong, C., Zhang, X., & Zhang, X. (2026) · Diabetes, Metabolic Syndrome and Obesity · doi:10.2147/dmso.s573711
- Authors
- Xu, J., Nakamura, M. T., Cho, H. P., & Clarke, S. D.
- Affiliations
- The University of Texas at Austin (US)
- Corresponding author
- Clarke, Steven D.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1999-08
- Volume
- 274
- Issue
- 33
- Pages
- 23577-23583
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2040735050
- Cited by
- 499
- References
- 1
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 6 · 2023: 11 · 2022: 8 · 2021: 6 · 2020: 18 · 2019: 10 · 2018: 10 · 2017: 8 · 2016: 15 · 2015: 13 · 2014: 20 · 2013: 21 · 2012: 15
- FWCI
- 29.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- University of Texas at Austin
- National Institutes of Health (5r01dk052573-03, 5f32dk009723-02)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 09723, DK 52573, R01DK053872, DK-53872)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- SREBP1, polyunsaturated fatty acids, fatty acid synthase, hepatic lipogenesis, omega-6 fatty acids, omega-3 fatty acids, triolein, PPARα, Wy-14,643, post-transcriptional regulation, upstream stimulatory factor 1, dietary fatty acids
- MeSH terms
- Cell Line, Dietary Fats, DNA-Binding Proteins, Fatty Acids, Unsaturated, Gene Expression Regulation, Humans, Nuclear Proteins, Pyrimidines, RNA, Messenger, Transcription Factors, Peroxisome Proliferators, CCAAT-Enhancer-Binding Proteins, Sterol Regulatory Element Binding Protein 1
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