Role of Insulin in the Regulation of Proprotein Convertase Subtilisin/Kexin Type 9.
Role of Insulin in the Regulation of Proprotein Convertase Subtilisin/Kexin Type 9.
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DOI：
10.1161/atvbaha.115.305688
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发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
Biddinger SB
中科院分区：
文献类型：
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作者：
Miao J;Manthena PV;Haas ME;Ling AV;Shin DJ;Graham MJ;Crooke RM;Liu J;Biddinger SB
前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK 9）结合低密度脂蛋白（LDL）受体并靶向其降解，已成为血清胆固醇水平和心血管疾病风险的重要调节剂。尽管目前许多工作都集中在开发抑制PCSK 9的疗法上，但PCSK 9的内源性调节，特别是胰岛素的内源性调节，仍不清楚。这些研究的目的是确定胰岛素在体外和体内对PCSK 9的影响。使用大鼠肝癌细胞和原代大鼠肝细胞，我们发现胰岛素以PCSK 9依赖性方式增加PCSK 9表达和增加LDL受体降解。与此同时，肝脏特异性敲除胰岛素受体的小鼠的肝脏Pcsk 9 mRNA和血浆PCSK 9蛋白水平降低了55-75%;链脲佐菌素导致胰岛素缺乏的小鼠降低了75-88%;用胰岛素受体反义寡核苷酸治疗的ob/ob小鼠降低了65%。然而，反义寡核苷酸介导的胰岛素受体敲低瘦，野生型小鼠几乎没有影响。此外，我们发现，即使在缺乏肝脏胰岛素信号传导的小鼠中，禁食也能够将PCSK 9表达降低80%。综上所述，这些数据表明，虽然胰岛素诱导PCSK 9表达，但在所有条件下，它不是PCSK 9的唯一或甚至主导调节剂。
Proprotein convertase subtilisin/kexin type 9 (PCSK9), which binds the low density lipoprotein (LDL) receptor and targets it for degradation, has emerged as an important regulator of serum cholesterol levels and cardiovascular disease risk. Although much work is currently focused on developing therapies for inhibiting PCSK9, the endogenous regulation of PCSK9, particularly by insulin, remains unclear. The objective of these studies was to determine the effects of insulin on PCSK9 in vitro and in vivo. Using rat hepatoma cells and primary rat hepatocytes, we found that insulin increased PCSK9 expression and increased LDL receptor degradation in a PCSK9-dependent manner. In parallel, hepatic Pcsk9 mRNA and plasma PCSK9 protein levels were reduced by 55-75% in mice with liver-specific knockout of the insulin receptor; 75-88% in mice made insulin deficient with streptozotocin; and 65% in ob/ob mice treated with antisense oligonucleotides against the insulin receptor. However, antisense olignonucleotide mediated knockdown of insulin receptor in lean, wildtype mice had little effect. In addition, we found that fasting was able to reduce PCSK9 expression by 80% even in mice that lack hepatic insulin signaling. Taken together, these data indicate that though insulin induces PCSK9 expression, it is not the sole or even dominant regulator of PCSK9 under all conditions.