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Hepatic Glucagon Signaling Regulates PCSK9 and Low-Density Lipoprotein Cholesterol
- Source :
- Circulation Research. 124:38-51
- Publication Year :
- 2019
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2019.
-
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.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
Physiology
Cholesterol
PCSK9
Low density lipoprotein cholesterol
030209 endocrinology & metabolism
Lipid metabolism
Glucagon
03 medical and health sciences
chemistry.chemical_compound
030104 developmental biology
0302 clinical medicine
Endocrinology
chemistry
Internal medicine
medicine
Glucose homeostasis
Cardiology and Cardiovascular Medicine
Homeostasis
Hormone
Subjects
Details
- ISSN :
- 15244571 and 00097330
- Volume :
- 124
- Database :
- OpenAIRE
- Journal :
- Circulation Research
- Accession number :
- edsair.doi...........5be297af70e3d3e17ca1bd36d0375871