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Hepatic Glucagon Signaling Regulates PCSK9 and Low-Density Lipoprotein Cholesterol
Abstract
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.
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“Moreover, an in-depth analysis of these DEGs revealed significant enrichment in pathways including the cAMP signaling pathway, Rap1 signaling pathway, cGMP-PKG signaling pathway, Phospholipase D signaling pathway, insulin signaling pathway, insulin resistance, Glucagon signaling pathway and PPAR signaling pathway, which were closely implicated in lipid metabolism, as supported by previous studies”
From ABCC4 impairs the clearance of plasma LDL cholesterol through suppressing LDLR expression in the liver (2025) · cites this paper as [45]
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“Furthermore, cAMP and its downstream signaling pathways are known to regulate PCSK9 homeostasis and LOX-1 expression45,46.”
From ABCC4 impairs the clearance of plasma LDL cholesterol through suppressing LDLR expression in the liver (2025) · cites this paper as [45]
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“Given previous reports linking glucagon signaling to PCSK9 regulation45,71”
From ABCC4 impairs the clearance of plasma LDL cholesterol through suppressing LDLR expression in the liver (2025) · cites this paper as [45]
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“Several lines of evidence has conceived that EPAC2 plays significant roles in the liver45,71,96, endocrine glands and brain97–99.”
From ABCC4 impairs the clearance of plasma LDL cholesterol through suppressing LDLR expression in the liver (2025) · cites this paper as [45]
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Metadata
- Authors
- Spolitu, S., Okamoto, H., Dai, W., Zadroga, J. A., Wittchen, E. S., Gromada, J., & Ozcan, L.
- Venue
- Circulation Research
- Published
- 2019-01-04
- Volume
- 124
- Issue
- 1
- Pages
- 38-51
- ISSN
- 0009-7330
- 1524-4571
- PMC
- PMC6457439
- Cited by
- 64
- References
- 13
- Language
- en
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