Document Detail


Gli1 activation and protection against hepatic encephalopathy is suppressed by circulating transforming growth factor β1 in mice.
MedLine Citation:
PMID:  25046848     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
BACKGROUND & AIMS: Hepatic encephalopathy (HE) is a neurologic disorder that develops during liver failure. Few studies exist investigating systemic-central signalling during HE outside of inflammatory signalling. The transcription factor Gli1, which can be modulated by hedgehog signalling or transforming growth factor β1 (TGFβ1) signalling, has been shown to be protective in various neuropathies. We measured Gli1 expression in brain tissues from mice and evaluated how circulating TGFβ1 and canonical hedgehog signalling regulate its activation.
METHODS: Mice were injected with azoxymethane (AOM) to induce liver failure and HE in the presence of Gli1 vivo-morpholinos, the hedgehog inhibitor cyclopamine, Smoothened vivo-morpholinos, a Smoothened agonist, or TGFβ-neutralizing antibodies. Molecular analyses were used to assess Gli1, hedgehog signalling, and TGFβ1 signalling in the liver and brain of AOM mice and HE patients.
RESULTS: Gli1 expression was increased in brains of AOM mice and in HE patients. Intra-cortical infusion of Gli1 vivo-morpholinos exacerbated the neurologic deficits of AOM mice. Measures to modulate hedgehog signalling had no effect on HE neurological decline. Levels of TGFβ1 increased in the liver and serum of mice following AOM administration. TGFβ neutralizing antibodies slowed neurologic decline following AOM administration without significantly affecting liver damage. TGFβ1 inhibited Gli1 expression via a SMAD3-dependent mechanism. Conversely, inhibiting TGFβ1 increased Gli1 expression.
CONCLUSIONS: Cortical activation of Gli1 protects mice from induction of HE. TGFβ1 suppresses Gli1 in neurons via SMAD3 and promotes the neurologic decline. Strategies to activate Gli1 or inhibit TGFβ1 signalling might be developed to treat patients with HE.
Authors:
Matthew McMillin; Cheryl Galindo; Hae Yong Pae; Gabriel Frampton; Pier Luigi Di Patre; Matthew Quinn; Eric Whittington; Sharon DeMorrow
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Publication Detail:
Type:  Journal Article     Date:  2014-07-18
Journal Detail:
Title:  Journal of hepatology     Volume:  61     ISSN:  1600-0641     ISO Abbreviation:  J. Hepatol.     Publication Date:  2014 Dec 
Date Detail:
Created Date:  2014-12-03     Completed Date:  -     Revised Date:  2014-12-04    
Medline Journal Info:
Nlm Unique ID:  8503886     Medline TA:  J Hepatol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  1260-6     Citation Subset:  IM    
Copyright Information:
Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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Grant Support
ID/Acronym/Agency:
K01 DK078532/DK/NIDDK NIH HHS; R01 DK082435/DK/NIDDK NIH HHS

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