The CGRP receptor component RAMP1 links sensory innervation with YAP activity in the regenerating liver.
Adaptor Proteins, Signal Transducing
/ metabolism
Animals
Calcitonin Gene-Related Peptide
/ metabolism
Cell Cycle
/ physiology
Cell Cycle Proteins
/ metabolism
Cell Proliferation
/ physiology
Hepatectomy
/ methods
Hepatocytes
/ metabolism
Humans
Liver
/ metabolism
Liver Diseases
/ metabolism
Liver Regeneration
/ physiology
Male
Mice
Mice, Inbred C57BL
Phosphorylation
/ physiology
Receptor Activity-Modifying Protein 1
/ metabolism
Receptors, Calcitonin Gene-Related Peptide
/ metabolism
Signal Transduction
/ physiology
YAP-Signaling Proteins
CGRP
RAMP1
YAP/TAZ
liver regeneration
sensory innervation
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
24
12
2019
revised:
26
03
2020
accepted:
02
04
2020
pubmed:
25
4
2020
medline:
20
1
2021
entrez:
25
4
2020
Statut:
ppublish
Résumé
The effectiveness of liver regeneration limits surgical therapies of hepatic disorders and determines patient outcome. Here, we investigated the role of the neuropeptide calcitonin gene-related peptide (CGRP) for liver regeneration after acute or chronic injury. Mice deficient for the CGRP receptor component receptor activity-modifying protein 1 (RAMP1) were subjected to a 70% partial hepatectomy or repeated intraperitoneal injections of carbon tetrachloride. RAMP1 deficiency severely impaired recovery of organ mass and hepatocyte proliferation after both acute and chronic liver injury. Mechanistically, protein expression of the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) was decreased in regenerating livers of RAMP1-deficient mice. Lack of RAMP1 was associated with hyperphosphorylation of YAP on Ser127 and Ser397, which regulates YAP functional activity and protein levels. Consequently, expression of various YAP-controlled cell cycle regulators and hepatocyte proliferation were severely reduced in the absence of RAMP1. In vitro, CGRP treatment caused increased YAP protein expression and a concomitant decline of YAP phosphorylation in liver tissue slice cultures of mouse and human origin and in primary human hepatocytes. Thus, our results indicate that sensory nerves represent a crucial control element of liver regeneration after acute and chronic injury acting through the CGRP-RAMP1 pathway, which stimulates YAP/TAZ expression and activity.
Identifiants
pubmed: 32329113
doi: 10.1096/fj.201903200R
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Cell Cycle Proteins
0
Ramp1 protein, mouse
0
Receptor Activity-Modifying Protein 1
0
Receptors, Calcitonin Gene-Related Peptide
0
YAP-Signaling Proteins
0
Yap1 protein, mouse
0
Calcitonin Gene-Related Peptide
JHB2QIZ69Z
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
8125-8138Informations de copyright
© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
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