E2F1 mediates sustained lipogenesis and contributes to hepatic steatosis
Pierre-Damien Denechaud, … , Jean-Sébastien Annicotte, Lluis Fajas
Pierre-Damien Denechaud, … , Jean-Sébastien Annicotte, Lluis Fajas
Published November 30, 2015
Citation Information: J Clin Invest. 2016;126(1):137-150. https://doi.org/10.1172/JCI81542.
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Research Article Metabolism

E2F1 mediates sustained lipogenesis and contributes to hepatic steatosis

Abstract

E2F transcription factors are known regulators of the cell cycle, proliferation, apoptosis, and differentiation. Here, we reveal that E2F1 plays an essential role in liver physiopathology through the regulation of glycolysis and lipogenesis. We demonstrate that E2F1 deficiency leads to a decrease in glycolysis and de novo synthesis of fatty acids in hepatocytes. We further demonstrate that E2F1 directly binds to the promoters of key lipogenic genes, including Fasn, but does not bind directly to genes encoding glycolysis pathway components, suggesting an indirect effect. In murine models, E2F1 expression and activity increased in response to feeding and upon insulin stimulation through canonical activation of the CDK4/pRB pathway. Moreover, E2F1 expression was increased in liver biopsies from obese, glucose-intolerant humans compared with biopsies from lean subjects. Finally, E2f1 deletion completely abrogated hepatic steatosis in different murine models of nonalcoholic fatty liver disease (NAFLD). In conclusion, our data demonstrate that E2F1 regulates lipid synthesis and glycolysis and thus contributes to the development of liver pathology.

Authors

Pierre-Damien Denechaud, Isabel C. Lopez-Mejia, Albert Giralt, Qiuwen Lai, Emilie Blanchet, Brigitte Delacuisine, Brandon N. Nicolay, Nicholas J. Dyson, Caroline Bonner, François Pattou, Jean-Sébastien Annicotte, Lluis Fajas

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Figure 8

E2f1 deletion in db/db mouse model decreases glycolytic and lipogenic programs.

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E2f1 deletion in db/db mouse model decreases glycolytic and lipogenic p...
(A) Plasma insulin levels in db/+ E2f1+/+, db/db E2f1+/+, and db/db E2f1–/– mice (n = 5–9). (B) Ser473 phosphorylation of AKT in the livers of db/db E2f1+/+ and db/db E2f1–/– mice. (C) Relative liver mRNA expression levels of the indicated genes in the annotated mouse genotypes (n = 4–6). (D) Western blot analyses of the expression of the indicated proteins in the livers of db/+ E2f1+/+, db/db E2f1+/+, and db/db E2f1–/– mice. *P < 0.05, by 2-tailed, unpaired t test.