Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through the inhibition of ChREBP nuclear protein translocation
Renaud Dentin, … , Jean Girard, Catherine Postic
Renaud Dentin, … , Jean Girard, Catherine Postic
Published October 3, 2005
Citation Information: J Clin Invest. 2005;115(10):2843-2854. https://doi.org/10.1172/JCI25256.
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Research Article Genetics

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

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.

Authors

Renaud Dentin, Fadila Benhamed, Jean-Paul Pégorier, Fabienne Foufelle, Benoit Viollet, Sophie Vaulont, Jean Girard, Catherine Postic

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Figure 4

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PUFAs suppress nuclear translocation of ChREBP in cultured hepatocytes. ...
PUFAs suppress nuclear translocation of ChREBP in cultured hepatocytes. After plating, hepatocytes were cultured for 24 hours in the presence of 5 mM glucose. Hepatocytes were then incubated for 24 hours in the presence of 5 or 25 mM glucose with or without 100 nM insulin and 100 nM dexamethasone containing or not 0.3 mM of albumin-bound linoleate. (A) Cytosolic and nuclear forms of ChREBP were measured. Representative Western blots of 4 independent cultures are shown. (B) Representative images of subcellular localization of GFP-fused ChREBP under 5 mM glucose with or without 100 nM insulin; and 25 mM glucose plus 100 nM insulin with or without 0.3 mM of albumin-bound stearate (C18), oleate [C18:1 (n-9)], linoleate [C18:2 (n-6)], EPA [C20:5 (n-3)], or DHA [C22:6 (n-3)]. For each condition, hepatocyte nuclei were specifically stained using DAPI (right panels). Scale bar, 10 μM.