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E2F1 inhibits circulating cholesterol clearance by regulating Pcsk9 expression in the liver

Abstract : Cholesterol accumulation in the liver is an early event in nonalcoholic fatty liver disease (NAFLD). Here, we demonstrate that E2F1 plays a crucial role in maintaining cellular cholesterol homeostasis by regulating cholesterol uptake via proprotein convertase subtilisin/kexin 9 (PCSK9), an enzyme that promotes low-density lipoprotein receptor (LDLR) degradation upon activation. E2f1-/- mice display reduced total plasma cholesterol levels and increased cholesterol content in the liver. In this study, we show that E2f1 deletion in cellular and mouse models leads to a marked decrease in Pcsk9 expression and an increase in LDLR expression. In addition to the upregulation of LDLR, we report that E2f1-/- hepatocytes exhibit increased LDL uptake. ChIP-Seq and PCSK9 promoter reporter experiments confirmed that E2F1 binds to and transactivates the PCSK9 promoter. Interestingly, E2f1-/- mice fed a high-cholesterol diet (HCD) display a fatty liver phenotype and liver fibrosis, which is reversed by reexpression of PCSK9 in the liver. Collectively, these data indicate that E2F1 regulates cholesterol uptake and that the loss of E2F1 leads to abnormal cholesterol accumulation in the liver and the development of fibrosis in response to an HCD.
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https://hal.archives-ouvertes.fr/hal-01828864
Contributor : Stephanie Chatel <>
Submitted on : Tuesday, July 24, 2018 - 11:23:59 AM
Last modification on : Monday, July 20, 2020 - 12:34:52 PM

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Qiuwen Lai, Albert Giralt, Cédric Le May, Lianjun Zhang, Bertrand Cariou, et al.. E2F1 inhibits circulating cholesterol clearance by regulating Pcsk9 expression in the liver. JCI Insight, American Society for Clinical Investigation, 2017, Equipe IV, 2 (10), ⟨10.1172/jci.insight.89729⟩. ⟨hal-01828864⟩

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