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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Key steps of glycolysis and pentose phosphate pathway are decreased by P...
Key steps of glycolysis and pentose phosphate pathway are decreased by PUFAs both in vivo and in vitro. In vivo studies: Mice were fasted for 24 hours and then refed 18 hours on a HCHO-triolein or HCHO-PUFA diet. In vitro studies: 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 100 nM insulin in the presence or not of 0.3 mM of albumin-bound linoleate [C18:2 (n-6)]. (A) GK protein content and activity and G6P concentrations in vivo. Results are presented as the mean ± SEM; n = 6/group. *Significantly different from mice refed a HCHO diet for 18 hours (P < 0.005). (B) GK protein content and activity and G6P concentrations were measured in vitro. Results are mean ± SEM of values obtained from 4 independent cultures. #Significantly different from 25 mM glucose plus insulin (P < 0.005). (C) G6PDH activity and X5P concentrations in vivo and in vitro. Results are presented as the mean ± SEM; n = 6/group. *Significantly different from mice refed a HCHO diet for 18 hours (P < 0.005). #Significantly different from 25 mM glucose plus insulin (P < 0.005).