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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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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Dietary PUFAs suppress the hepatic abundance of ChREBP mRNA and ChREBP t...
Dietary PUFAs suppress the hepatic abundance of ChREBP mRNA and ChREBP total and nuclear protein content. (A) RTQ-PCR analysis of glycolytic and lipogenic genes from livers of 24 hour–fasted mice and mice refed a HCHO-triolein or HCHO-PUFA diet for 18 hours were performed. Results are the mean ± SEM; n = 6/group. *Significantly different from mice refed a HCHO diet for 18 hours (P < 0.005). (B) Insulin-stimulated liver lysates from 18 hour HCHO-, HCHO-triolein–, and HCHO-PUFA–fed mice blotted with anti–phospho-Akt (P-Akt) and anti–phospho-MAPK antibodies. Blots were then stripped and reprobed for total Akt and MAPK. n = 3/group. (C) Total, cytosolic, and nuclear ChREBP, precursor SREBP-1 (pSREBP-1), and mature SREBP-1 (mSREBP-1) protein, in cytosolic and nuclear extracts from livers of 24 hour–fasted and 18 hour–refed mice on a HCHO diet supplemented or not with PUFAs. β-Actin and Lamin A/C antibodies were used as loading controls. A representative Western blot is shown. n = 6/group.