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The lower risk of coronary artery disease in premenopausal women than in men and postmenopausal women implicates sex steroids in cardioprotective processes. β‐Estradiol upregulates liver low‐density lipoprotein receptor ( LDLR ), which, in turn, decreases circulating levels of low‐density lipoprotein, which is a risk factor for coronary artery disease. Conversely,  LDLR  protein is negatively regulated by proprotein convertase subtilisin/kexin type 9 ( PCSK 9). Herein, we investigated  PCSK 9 regulation by β‐estradiol and its impact on  LDLR  in human hepatocarcinoma HuH7 cells grown in the presence or absence of β‐estradiol. Immunoblot analysis showed upregulation of  LDLR  at 3 μ m  β‐estradiol (140%), and the upregulation reached 220% at 10 μ m  β‐estradiol; only at the latter dose was an increase in   LDLR    mRNA  detected by  qPCR , suggesting post‐translational regulation of  LDLR . No changes in  PCSK 9  mRNA  or secreted protein levels were detected by  qPCR  or  ELISA , respectively. β‐estradiol‐conditioned medium devoid of  PCSK 9 failed to upregulate  LDLR . Similarly,   PCSK 9  knockdown cells showed no upregulation of  LDLR  by β‐estradiol. Together, these results indicate a requirement for  PCSK 9 in the β‐estradiol‐induced upregulation of  LDLR . A radiolabeling assay showed a significant, dose‐dependent decrease in the ratio of secreted phospho PCSK 9 to total secreted  PCSK 9 with increasing β‐estradiol levels, suggesting a change in the functional state of  PCSK 9 in the presence of β‐estradiol. Our results indicate that the protein upregulation of  LDLR  at subtranscriptionally effective doses of β‐estradiol, and its supratranscriptional upregulation at 10 μ m  β‐estradiol, occur through an extracellular  PCSK 9‐dependent mechanism.

the febs journal

β‐Estradiol results in a proprotein convertase subtilisin/kexin type 9‐dependent increase in low‐density lipoprotein receptor levels in human hepatic HuH7 cells