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Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through the inhibition of ChREBP nuclear protein translocation
Open accessAbstract
Dietary polyunsaturated fatty acids (PUFAs) are potent inhibitors of hepatic glycolysis and lipogenesis. Recently, carbohydrate-responsive element-binding protein (ChREBP) was implicated in the regulation by glucose of glycolytic and lipogenic genes, including those encoding L-pyruvate kinase (L-PK) and fatty acid synthase (FAS). The aim of our study was to assess the role of ChREBP in the control of L-PK and FAS gene expression by PUFAs. We demonstrated in mice, both in vivo and in vitro, that PUFAs [linoleate (C18:2), eicosapentanoic acid (C20:5), and docosahexaenoic acid (C22:6)] suppressed ChREBP activity by increasing ChREBP mRNA decay and by altering ChREBP translocation from the cytosol to the nucleus, independently of an activation of the AMP-activated protein kinase, previously shown to regulate ChREBP activity. In contrast, saturated [stearate (C18)] and monounsaturated fatty acids [oleate (C18:1)] had no effect. Since glucose metabolism via the pentose phosphate pathway is determinant for ChREBP nuclear translocation, the decrease in xylulose 5-phosphate concentrations caused by a PUFA diet favors a PUFA-mediated inhibition of ChREBP translocation. In addition, overexpression of a constitutive nuclear ChREBP isoform in cultured hepatocytes significantly reduced the PUFA inhibition of both L-PK and FAS gene expression. Our results demonstrate that the suppressive effect of PUFAs on these genes is primarily caused by an alteration of ChREBP nuclear translocation. In conclusion, we describe a novel mechanism to explain the inhibitory effect of PUFAs on the genes encoding L-PK and FAS and demonstrate that ChREBP is a pivotal transcription factor responsible for coordinating the PUFA suppression of glycolytic and lipogenic genes.
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“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”
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A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver
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REGULATION OF GENE EXPRESSION BY DIETARY FAT
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ADD1/SREBP-1c Is Required in the Activation of Hepatic Lipogenic Gene Expression by Glucose
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Self-citationUnsaturated Fatty Acids Down-regulate SREBP Isoforms 1a and 1c by Two Mechanisms in HEK-293 Cells
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Metadata
- Authors
- Dentin, R.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Dentin, R.
- ORCID
- Dentin, R.
- Venue
- Journal of Clinical Investigation
- Published
- 2005-10-01
- Volume
- 115
- Issue
- 10
- Pages
- 2843-2854
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1224299
- OpenAlex
- W2114472618
- Cited by
- 315
- References
- 50
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 11 · 2023: 15 · 2022: 12 · 2021: 15 · 2020: 19 · 2019: 8 · 2018: 14 · 2017: 14 · 2016: 18 · 2015: 19 · 2014: 9 · 2013: 23 · 2012: 13
- FWCI
- 16.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- European Commission (LSHMCT-2004-005272)
- Ministère de l'Enseignement Supérieur et de la Recherche
- 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 › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- polyunsaturated fatty acids, ChREBP, nuclear translocation, hepatic glycolysis, lipogenesis, fatty acid synthase, mRNA degradation, xylulose-5-phosphate, pentose phosphate pathway, glucose metabolism, AMPK, linoleic acid, eicosapentaenoic acid, docosahexaenoic acid, saturated fatty acids, monounsaturated fatty acids, hepatocytes, transcriptional regulation
- MeSH terms
- Animals, Cells, Cultured, Dietary Fats, Unsaturated, Docosahexaenoic Acids, Glycolysis, Male, Multienzyme Complexes, Nuclear Proteins, Pentose Phosphate Pathway, Pyruvate Kinase, Transcription Factors, Eicosapentaenoic Acid, Down-Regulation, Gene Expression Regulation, Enzymologic, Protein Serine-Threonine Kinases, Hepatocytes, Lipogenesis, Mice, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, AMP-Activated Protein Kinases, Fatty Acid Synthases
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