Cited by 315Fatty Acid Research and HealthLipid metabolism and biosynthesisDiet, Metabolism, and Disease

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Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through the inhibition of ChREBP nuclear protein translocation

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Dentin, R.·2005·Journal of Clinical Investigation

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Abstract

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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Authors: Dentin, R.
Affiliations: Centre National de la Recherche Scientifique (FR)
Corresponding author: Dentin, R.
ORCID: Dentin, R.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2005-10-01
Volume: 115
Issue: 10
Pages: 2843-2854
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci25256
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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Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through the inhibition of ChREBP nuclear protein translocation

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