The CGRP receptor component RAMP1 links sensory innervation with YAP activity in the regenerating liver

Abstract

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.

YAP/TAZ: Molecular pathway and disease therapy

“…In addition, further studies revealed that liver regeneration was diminished for the first 32 hours after YAP knockdown and then returned to the normal regeneration process, implying that YAP is only necessary for hepatocyte entry into the cell cycle, particularly the S phase, but not for the subsequent M phase 374 . Although YAP/TAZ is not a necessary factor for the subsequent phases of the cell cycle, calcitonin gene‐related peptide‐receptor activity‐modifying protein 1 (RAMP1) has been shown to stimulate the proliferative process by regulating YAP/TAZ activity during subsequent phases of hepatocyte proliferation 375 . One of the most common complications of hepatectomy is liver ischemia/reperfusion injury.…”

Neural dependency in wound healing and regeneration

“…Neonatal mouse heart, zebrafish heart Cardiomyocyte proliferation NRG1, ACh Mahmoud et al 221 Gemberling et al 222 Kreipke and Birren 226 Rat liver Hepatocyte proliferation Neurotransmitters: ACh, NE Ohtake et al 232 Izumi et al 234 Ohtake 230 Mouse liver Hepatocyte proliferation CGRP signaling Laschinger et al 233 In vitro hepatic stellate cells ECM deposition and HSC proliferation α-adrenergic signaling Sigala et al 236 Oben et al 237 Coculture rat sensory neurons and human corneal fibroblasts MMP expression IL-6 signaling Ko et al 144 Mouse salivary gland Tissue regeneration Unknown parasympathetic neurotrophic factor…”

Hepatic Nervous System in Development, Regeneration, and Disease

“…( 36 ) RAMP1 is a component of the CGRP receptor, and RAMP1 knockout mice show decreased hepatocyte proliferation and significantly delayed regeneration following partial hepatectomy. ( 37 )…”

“…(36) RAMP1 is a component of the CGRP receptor, and RAMP1 knockout mice show decreased hepatocyte proliferation and significantly delayed regeneration following partial hepatectomy. (37) toXIC INJURy MoDelS Data from toxic injury models indicate that the sympathetic nervous system exerts a pro-inflammatory, profibrotic effect by acting on hepatic stellate cells (HSCs). Sympathetic nerves are in close proximity to HSCs, and activated HSCs express α-adrenergic and β-adrenergic receptors, as well as receptors for neuropeptide Y.…”