Gli1 activation and protection against hepatic encephalopathy is suppressed by circulating transforming growth factor β1 in mice

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 beta 1 (TGF beta 1) signalling, has been shown to be protective in various neuropathies. We measured Gli1 expression in brain tissues from mice and evaluated how circulating TGF beta 1 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 TGF beta-neutralizing antibodies. Molecular analyses were used to assess Gli1, hedgehog signalling, and TGF beta 1 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 TGF beta 1 increased in the liver and serum of mice following AOM administration. TGF beta-neutralizing antibodies slowed neurologic decline following AOM administration without significantly affecting liver damage. TGF beta 1 inhibited Gli1 expression via a SMAD3-dependent mechanism. Conversely, inhibiting TGF beta 1 increased Gli1 expression. Conclusions: Cortical activation of Gli1 protects mice from induction of HE. TGF beta 1 suppresses Gli1 in neurons via SMAD3 and promotes the neurologic decline. Strategies to activate Gli1 or inhibit TGF beta 1 signalling might be developed to treat patients with HE. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.