Fasting induces hyperlipidemia in mice overexpressing proprotein convertase subtilisin kexin type 9: Lack of modulation of very-low-density lipoprotein hepatic output by the low-density lipoprotein receptor
Fasting induces hyperlipidemia in mice overexpressing proprotein convertase subtilisin kexin type 9: Lack of modulation of very-low-density lipoprotein hepatic output by the low-density lipoprotein receptor
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DOI：
10.1210/en.2006-0098
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发表时间：
2006-10-01
期刊：
影响因子：
4.8
通讯作者：
Costet, Philippe
中科院分区：
文献类型：
--
作者：
Lambert, Gilles;Jarnoux, Anne-Laure;Costet, Philippe
几种枯草杆菌蛋白转换酶9(PCSK9)基因突变作为低密度脂蛋白受体(LDLR)的负调节因子，可导致家族性高胆固醇血症。在这里，我们发现在饮食挑战时，低密度脂蛋白受体的下调也是PCSK9调节肝脏产生含载脂蛋白B的脂蛋白的关键机制。因此，腺病毒介导的PCSK9在禁食24小时的小鼠中的过度表达导致了大量的高脂血症，这是由于极低密度脂蛋白(VLDL)甘油三酯和载脂蛋白B100肝脏产量的显著增加。对LDLR(-/-)小鼠的类似研究表明，PCSK9介导的禁食状态下极低密度脂蛋白输出的改变需要LDLR。极低密度脂蛋白产量的增加与肝脏内脂肪储存的减少以及过氧化体增殖物激活的受体-α活性和靶基因表达的下调有关。最后，我们发现低甘油三酯的过氧化体增殖物激活受体-α激动剂非诺贝特抑制了PCSK9的肝脏表达。综上所述，PCSK9对低密度脂蛋白受体表达的负性调节，降低了血浆低密度脂蛋白的清除，也促进了禁食后体内新生极低密度脂蛋白的过量产生。
Several proprotein convertase subtilisin kexin type 9 (PCSK9) mutations lead to familial hypercholesterolemia by virtue of its role as a negative modulator of the low-density lipoprotein receptor (LDLr). Here, we uncover that upon dietary challenge, the down-regulation of the LDLr is also a key mechanism by which PCSK9 modulates the hepatic production of apolipoprotein-B-containing lipoproteins. Thus, adenoviral-mediated overexpression of PCSK9 in 24-h fasted mice results in massive hyperlipidemia, due to a striking increase in very-low-density lipoprotein (VLDL) triglycerides and apolipoprotein B100 hepatic output. Similar studies in LDLr (-/-) mice demonstrate that PCSK9-mediated alteration of VLDL output in the fasted state requires the LDLr. This increased production of VLDL was associated with a concomitant reduction of intrahepatic lipid stores as well as a lack of down-regulation of peroxisome proliferator-activated receptor-alpha activity and target genes expression. Finally, we show that PCSK9 hepatic expression is inhibited by the hypotriglyceridemic peroxisome proliferator-activated receptor-alpha agonist fenofibrate. In summary, the negative modulation of LDLr expression by PCSK9, which decreases plasma LDL clearance, also promotes an overproduction of nascent VLDL in vivo upon fasting.