E2F1 inhibits circulating cholesterol clearance by regulating Pcsk9 expression in the liver
Qiuwen Lai, Albert Giralt, Cédric Le May, Lianjun Zhang, Bertrand Cariou, Pierre-Damien Denechaud, Lluis Fajas
Qiuwen Lai, Albert Giralt, Cédric Le May, Lianjun Zhang, Bertrand Cariou, Pierre-Damien Denechaud, Lluis Fajas
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Research Article Hepatology Metabolism

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.

Authors

Qiuwen Lai, Albert Giralt, Cédric Le May, Lianjun Zhang, Bertrand Cariou, Pierre-Damien Denechaud, Lluis Fajas

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Figure 1

Decreased total plasma cholesterol levels and increased cholesterol content in the liver and colon tissues of E2f1–/– mice.

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Decreased total plasma cholesterol levels and increased cholesterol cont...
(A) Plasma lipid profiles of E2f1+/+ and E2f1–/– mice fed a normal chow diet. n = 8–10 mice per group. (B) Quantification of total free cholesterol levels in feces collected from individual mice using commercial kits. n = 5 mice per group. (C) Quantification of total bile acid (BA) levels in feces collected from individual mice using commercial kits. n = 5–6 mice per group. (D) Quantification of the cholesterol content of various tissues from E2f1+/+ and E2f1–/– mice fed a chow diet. BAT, Brown adipose tissue. n = 5–6 mice per group. All data are presented as the mean ± SEM. Differences between E2f1+/+ and E2f1–/– were determined by 2-tailed unpaired t test. *P < 0.05, **P < 0.01, ****P < 0.0001.