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 6

Insulin regulates E2F1 activity through RB1 and CDK4.

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Insulin regulates E2F1 activity through RB1 and CDK4. (A) Relative E2f1 ...
(A) Relative E2f1 mRNA expression levels in the livers of mice after a 24-hour fast, followed by an 18-hour refeeding. (B) Protein expression analyses of the indicated cellular fractions in the livers of mice under the same conditions as in A. (C) E2F reporter activity (E2FRE-TK-luc) in response to insulin in HEK293T cells. (D) Mouse Fasn promoter activity in HepG2 cells transfected with empty vector, E2F1, or RB1. (E) Ser780 phosphorylation of RB1 in the livers of fasted and refed mice. (F) Ser780 phosphorylation of RB1 in hepatocytes after 1 hour of insulin stimulation. (G) RB1 co-IP with E2F1 after 1 hour of insulin stimulation in HepG2 hepatocytes. (H) Relative mRNA expression of the indicated genes in hepatocytes treated with adenovirus expressing sh-control or sh-CDK4 and stimulated for 24 hours with G5 or G25i. (I) Protein levels of ACACA, FASN, and CDK4 in hepatocytes treated with adenovirus expressing sh-control or sh-CDK4 and stimulated for 24 hours with G5 or G25i. The experiments were performed at least 3 times. *P < 0.05, by 2-tailed, unpaired t test.