Hepatic Glucagon Signaling Regulates PCSK9 and Low-Density Lipoprotein Cholesterol
Hepatic Glucagon Signaling Regulates PCSK9 and Low-Density Lipoprotein Cholesterol
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DOI：
10.1161/circresaha.118.313648
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发表时间：
2019-01-04
影响因子：
20.1
通讯作者：
Ozcan, Lale
中科院分区：
文献类型：
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作者：
Spolitu, Stefano;Okamoto, Haruka;Ozcan, Lale
原理：胰高血糖素是调节空腹适应性代谢反应的关键激素。胰高血糖素除了维持葡萄糖稳态外，还参与调节胆固醇代谢；然而，这种效应背后的分子途径尚不完全清楚。目的：我们试图确定肝胰高血糖素受体（Gcgr）信号在血浆胆固醇调节中的作用，并确定其潜在的分子机制。方法和结果：我们发现Gcgr信号通过调节PCSK9（蛋白转化酶枯草素/ keexin 9型）水平在LDL-C（低密度脂蛋白胆固醇）稳态中起重要作用。沉默肝脏Gcgr或抑制胰高血糖素的作用可增加肝脏和血浆PCSK9，并导致LDL受体蛋白降低和血浆LDL- c升高。相反，用胰高血糖素治疗野生型（WT）小鼠降低了LDL-C水平，而在Pcsk9-/和Ldlr-/-小鼠中，这种反应被消除。我们的功能获得和功能丧失研究发现Epac2（由cAMP-2激活的交换蛋白）和Rap1 （ras相关蛋白-1）是胰高血糖素作用于PCSK9稳态的下游介质。此外，机制研究表明，胰高血糖素在不改变PCSK9 mRNA水平的情况下影响PCSK9蛋白的半衰期，表明Gcgr信号通路调节PCSK9的降解。结论：这些发现为肝胰高血糖素信号传导与脂质代谢之间的分子相互作用提供了新的见解，并描述了PCSK9调控的新的转录后机制。
Rationale: Glucagon is a key hormone that regulates the adaptive metabolic responses to fasting. In addition to maintaining glucose homeostasis, glucagon participates in the regulation of cholesterol metabolism; however, the molecular pathways underlying this effect are incompletely understood.Objective: We sought to determine the role of hepatic Gcgr (glucagon receptor) signaling in plasma cholesterol regulation and identify its underlying molecular mechanisms.Methods and Results: We show that Gcgr signaling plays an essential role in LDL-C (low-density lipoprotein cholesterol) homeostasis through regulating the PCSK9 (proprotein convertase subtilisin/ kexin type 9) levels. Silencing of hepatic Gcgr or inhibition of glucagon action increased hepatic and plasma PCSK9 and resulted in lower LDLR (LDL receptor) protein and increased plasma LDL-C. Conversely, treatment of wild-type (WT) mice with glucagon lowered LDL-C levels, whereas this response was abrogated in Pcsk9-/-and Ldlr-/-mice. Our gain-and loss-of-function studies identified Epac2 (exchange protein activated by cAMP-2) and Rap1 (Ras-related protein-1) as the downstream mediators of glucagon's action on PCSK9 homeostasis. Moreover, mechanistic studies revealed that glucagon affected the half-life of PCSK9 protein without changing the level of its mRNA, indicating that Gcgr signaling regulates PCSK9 degradation.Conclusions: These findings provide novel insights into the molecular interplay between hepatic glucagon signaling and lipid metabolism and describe a new posttranscriptional mechanism of PCSK9 regulation.