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

JCI Insight
Qiuwen LaiLluis Fajas

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.

References

Apr 4, 1986·Science·M S Brown, J L Goldstein
Aug 8, 1998·Genes & Development·N Dyson
Sep 22, 1998·Current Biology : CB·M Accad, R V Farese
Jul 12, 2002·Developmental Cell·Lluis FajasJohan Auwerx
May 6, 2004·Journal of Cell Science·Maxim V Frolov, Nicholas J Dyson
Feb 23, 2008·The Journal of Clinical Investigation·Pierre-Damien DenechaudCatherine Postic
Apr 23, 2008·Current Protocols in Neuroscience·Patrick Salmon, Didier Trono
Aug 1, 2008·The Journal of Biological Chemistry·Michael C F HsiehZaher Nahlé
Mar 7, 2009·Arteriosclerosis, Thrombosis, and Vascular Biology·Cédric Le MayPhilippe Costet
Jul 21, 2011·Journal of Lipids·Klementina Fon Tacer, Damjana Rozman
Aug 16, 2011·Nature Cell Biology·Emilie BlanchetLluis Fajas
Dec 20, 2011·Cancer Research·Anup K Biswas, David G Johnson
May 2, 2012·The Journal of Clinical Investigation·Fadila BenhamedCatherine Postic
Dec 5, 2012·Progress in Lipid Research·Giovanni MussoMaurizio Cassader
Feb 13, 2013·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Arne DikkersUwe J F Tietge
Apr 26, 2013·Journal of Lipid Research·Rex A ParkerSiew P Ho
May 3, 2013·The Journal of Clinical Investigation·Detlef Schuppan, Yong Ook Kim
Dec 18, 2013·Science·Ophir ShalemFeng Zhang
Mar 13, 2014·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Yuxia ZhangLi Wang
Mar 19, 2014·EMBO Reports·Isabel C Lopez-MejiaJamal Tazi
Feb 6, 2015·Journal of Lipid Research·Vikram Ravindra ShendeJingwen Liu
Jun 2, 2015·Biochimica Et Biophysica Acta·Graciela ArguelloSilvana Zanlungo
Sep 4, 2015·The Journal of Pathology·Ilaria GiunzioniSergio Fazio
Dec 1, 2015·The Journal of Clinical Investigation·Pierre-Damien DenechaudLluis Fajas
Dec 26, 2015·Trends in Endocrinology and Metabolism : TEM·George N Ioannou

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Citations

Nov 28, 2017·Frontiers in Endocrinology·Pierre-Damien DenechaudAlbert Giralt
Mar 30, 2019·Current Opinion in Lipidology·Stefano SpolituLale Ozcan
Nov 22, 2019·Scientific Reports·Ji Soo LeeFalk W Lohoff
Jul 24, 2020·International Journal of Environmental Research and Public Health·Zheng LiLei Yang
Jan 13, 2021·International Journal of Molecular Sciences·Abirami RajavelMehmet Gültas
Jul 2, 2021·Human Molecular Genetics·Amy R BentleyCharles N Rotimi

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Datasets Mentioned

BETA
GSE74006
5

Methods Mentioned

BETA
ChIP
PCR
ChIP-seq
transfections
transfection

Software Mentioned

ChemiDoc XRS
GraphPad
Prism

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