TY - JOUR
T1 - Gli1 activation and protection against hepatic encephalopathy is suppressed by circulating transforming growth factor β1 in mice
AU - McMillin, Matthew
AU - Galindo, Cheryl
AU - Pae, Hae Yong
AU - Frampton, Gabriel
AU - Di Patre, Pier Luigi
AU - Quinn, Matthew
AU - Whittington, Eric
AU - Demorrow, Sharon
N1 - Funding Information:
This manuscript is the result of work supported with resources and the use of facilities at the Central Texas Veterans Health Care System, Temple, Texas. Tissues were received from the New South Wales Tissue Resource Centre at the University of Sydney, supported by the National Health and Medical Research Council of Australia, Schizophrenia Research Institute and the National Institute of Alcohol Abuse and Alcoholism ( NIH R24AA012725 ). The New South Wales Tissue Resource Centre obtained ethics approval from the Sydney Local Health Network Ethics Review Committee protocol number X011-0107. The authors would also like to acknowledge Leticia Fuentes and Amber Jacobs for their technical assistance on this project.
Funding Information:
The following study was funded by an R01 award ( NIH DK082435 ), an NIH K01 award ( DK078532 ) and a Scott & White Intramural grant award (No: 050339) to S. DeMorrow.
Publisher Copyright:
© 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
PY - 2014/12/1
Y1 - 2014/12/1
N2 - 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.
AB - 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.
KW - Acute liver failure
KW - Azoxymethane
KW - Hepatic encephalopathy
KW - SMAD3
KW - Sonic hedgehog
KW - TGFb1
UR - http://www.scopus.com/inward/record.url?scp=84922789090&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84922789090&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2014.07.015
DO - 10.1016/j.jhep.2014.07.015
M3 - Article
C2 - 25046848
AN - SCOPUS:84922789090
SN - 0168-8278
VL - 61
SP - 1260
EP - 1266
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 6
ER -