title: Gli1 activation and protection against hepatic encephalopathy is suppressed by circulating transforming growth factor β1 in mice.
abstract: OBJECTIVE
  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.affiliation: Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, TX, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: McMillin
authors.affiliation: Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, TX, United States.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Galindo
authors.affiliation: Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, TX, United States.
authors.forename: Hae Yong
authors.initials: HY
authors.lastname: Pae
authors.affiliation: Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, TX, United States.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Frampton
authors.affiliation: Department of Pathology, Texas A&M Health Science Center College of Medicine, TX, United States; Department of Pathology, Baylor Scott & White Health, TX, United States.
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Di Patre
authors.affiliation: Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, TX, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: Quinn
authors.affiliation: Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, TX, United States.
authors.forename: Eric
authors.initials: E
authors.lastname: Whittington
authors.affiliation: Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, TX, United States; Digestive Disease Research Center, TX, United States; Central Texas Veterans Health Care System, Temple, TX, United States. Electronic address: demorrow@medicine.tamhsc.edu.
authors.forename: Sharon
authors.initials: S
authors.lastname: DeMorrow
mesh_terms: D000818:Animals; D001344:Autopsy; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D004195:Disease Models, Animal; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism; D006501:Hepatic Encephalopathy / Q000378:metabolism* / Q000517:prevention & control*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D060172:Morpholinos / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051900:Smad3 Protein / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000097:blood*; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D060172:Morpholinos; D051900:Smad3 Protein; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D000071676:Zinc Finger Protein GLI1
keywords: Acute liver failure; Azoxymethane; Hepatic encephalopathy; SMAD3; Sonic hedgehog; TGFβ1