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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

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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 4

Glucose and lipid metabolism is impaired in E2f1–/– hepatocytes.

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Glucose and lipid metabolism is impaired in E2f1–/– hepatocytes.
(A) ECA...
(A) ECAR of E2f1+/+ and E2f1–/– hepatocytes after glucose treatment using a Seahorse analyzer (2 independent experiments, each with 8 technical replicates). (B) Glycogen content in E2f1 +/+ and E2f1 –/– hepatocytes treated for 24 hours with G5 or G25i. (C) Quantification of the incorporation of C14-labeled acetate in the TG fraction in hepatocytes treated for 24 hours with G5 or G25i from the indicated genotypes, as a measure of lipogenesis. (D) Representative Oil Red O staining of E2f1+/+ versus E2f1–/– hepatocytes (original magnification, ×200). Unless otherwise specified, all experiments represent the average of 3 independent experiments. *P < 0.05 compared with control, by 2-tailed, unpaired t test.

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