Persson Lena, Gälman Cecilia, Angelin Bo, Rudling Mats
Department of Endocrinology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Endocrinology. 2009 Mar;150(3):1140-6. doi: 10.1210/en.2008-1281. Epub 2008 Nov 13.
Hormonal or dietary challenge can stimulate hepatic low-density lipoprotein receptor (LDLR) expression through posttranscriptional mechanisms. We here tested whether such observations may be due to regulation of proprotein convertase subtilisin/kexin type 9 (PCSK9). Treatment with glucagon resulted in a 2-fold increase in hepatic LDLR protein expression, whereas its mRNA levels were reduced; this occurred simultaneously with a 70% reduction in PCSK9 expression. Insulin treatment resulted in responses opposite to those seen by treatment with glucagon. Furthermore, high-dose ethinylestradiol treatment reduced PCSK9 expression by half. Finally, feeding of rats with dietary cholesterol reduced PCSK9 expression, resulting in an increased number of hepatic LDLRs despite a reduction of LDLR mRNA levels. Regulation of PCSK9 occurred in part through sterol regulatory element binding protein-2, but changes in this cholesterol-controlled transcription factor could not explain all hormonal effects seen. We conclude that the hormonal and dietary regulation of hepatic LDLRs also involves posttranscriptional regulation by PCSK9. The identification of PCSK9 regulation by these various treatments is important in understanding of the physiological function of this protein and points to new targets for therapeutic treatments to increase hepatic LDLR numbers.
激素或饮食刺激可通过转录后机制刺激肝脏低密度脂蛋白受体（LDLR）的表达。我们在此测试了这些观察结果是否可能归因于前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK9）的调节。用胰高血糖素处理导致肝脏LDLR蛋白表达增加2倍，而其mRNA水平降低；与此同时，PCSK9表达降低了70%。胰岛素处理产生的反应与胰高血糖素处理相反。此外，高剂量乙炔雌二醇处理使PCSK9表达降低一半。最后，用膳食胆固醇喂养大鼠可降低PCSK9表达，尽管LDLR mRNA水平降低，但肝脏LDLR数量增加。PCSK9的调节部分通过固醇调节元件结合蛋白-2发生，但这种胆固醇控制的转录因子的变化并不能解释所有观察到的激素效应。我们得出结论，肝脏LDLR的激素和饮食调节也涉及PCSK9的转录后调节。通过这些不同处理确定PCSK9的调节对于理解该蛋白的生理功能很重要，并为增加肝脏LDLR数量的治疗提供了新靶点。
