β-Estradiol results in a proprotein convertase subtilisin/kexin type 9-dependent increase in low-density lipoprotein receptor levels in human hepatic HuH7 cells.
FEBS JOURNAL(2015)
摘要
The lower risk of coronary artery disease in premenopausal women than in men and postmenopausal women implicates sex steroids in cardioprotective processes. beta-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 (PCSK9). Herein, we investigated PCSK9 regulation by beta-estradiol and its impact on LDLR in human hepatocarcinoma HuH7 cells grown in the presence or absence of beta-estradiol. Immunoblot analysis showed upregulation of LDLR at 3 mu M beta-estradiol (140%), and the upregulation reached 220% at 10 mu M beta-estradiol; only at the latter dose was an increase in LDLR mRNA detected by qPCR, suggesting post-translational regulation of LDLR. No changes in PCSK9 mRNA or secreted protein levels were detected by qPCR or ELISA, respectively. beta-estradiol-conditioned medium devoid of PCSK9 failed to upregulate LDLR. Similarly, PCSK9 knockdown cells showed no upregulation of LDLR by beta-estradiol. Together, these results indicate a requirement for PCSK9 in the beta-estradiol-induced upregulation of LDLR. A radiolabeling assay showed a significant, dose-dependent decrease in the ratio of secreted phosphoPCSK9 to total secreted PCSK9 with increasing beta-estradiol levels, suggesting a change in the functional state of PCSK9 in the presence of beta-estradiol. Our results indicate that the protein upregulation of LDLR at subtranscriptionally effective doses of beta-estradiol, and its supratranscriptional upregulation at 10 mu M beta-estradiol, occur through an extracellular PCSK9-dependent mechanism.
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关键词
atherosclerosis,estrogen,lipoproteins/receptors,low-density lipoprotein receptor,proprotein convertase subtilisin/kexin type 9
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