GABA, γ-Aminobutyric Acid, Protects Against Severe Liver Injury

Toshiyuki Hata, Fatima Rehman, Tomohide Hori, Justin H Nguyen

Research output: Contribution to journalArticle

Abstract

Background: Acute liver failure (ALF) from severe acute liver injury is a critical condition associated with high mortality. The purpose of this study was to investigate the impact of preemptive administration of γ-aminobutyric acid (GABA) on hepatic injury and survival outcomes in mice with experimentally induced ALF. Materials and methods: To induce ALF, C57BL/6NHsd mice were administered GABA, saline, or nothing for 7 d, followed by intraperitoneal administration of 500 μg of tumor necrosis factor α and 20 mg of D-galactosamine. The study mice were humanely euthanized 4-5 h after ALF was induced or observed for survival. Proteins present in the blood samples and liver tissue from the euthanized mice were analyzed using Western blot and immunohistochemical and histopathologic analyses. For inhibition studies, we administered the STAT3-specific inhibitor, NSC74859, 90 min before ALF induction. Results: We found that GABA-treated mice had substantial attenuation of terminal deoxynucleotidyl transferase dUTP nick end labeling–positive hepatocytes and hepatocellular necrosis, decreased caspase-3, H2AX, and p38 MAPK protein levels and increased expressions of Jak2, STAT3, Bcl-2, and Mn-SOD, with improved mitochondrial integrity. The reduced apoptotic proteins led to a significantly prolonged survival after ALF induction in GABA-treated mice. The STAT3-specific inhibitor NSC74859 eliminated the survival advantage in GABA-treated mice with ALF, indicating the involvement of the STAT3 pathway in GABA-induced reduction in apoptosis. Conclusions: Our results showed that preemptive treatment with GABA protected against severe acute liver injury in mice via GABA-mediated STAT3 signaling. Preemptive administration of GABA may be a useful approach to optimize marginal donor livers before transplantation.

LanguageEnglish (US)
Pages172-183
Number of pages12
JournalJournal of Surgical Research
Volume236
DOIs
StatePublished - Apr 1 2019

Fingerprint

gamma-Aminobutyric Acid
Acute Liver Failure
Liver
Wounds and Injuries
NSC 74859
Galactosamine
Proteins
DNA Nucleotidylexotransferase
p38 Mitogen-Activated Protein Kinases
Inbred C57BL Mouse
Caspase 3
Liver Transplantation
Superoxide Dismutase
Hepatocytes
Necrosis
Tumor Necrosis Factor-alpha
Western Blotting
Apoptosis
Mortality

Keywords

  • Acute liver failure
  • GABA
  • NSC74859
  • STAT3 signaling

ASJC Scopus subject areas

  • Surgery

Cite this

GABA, γ-Aminobutyric Acid, Protects Against Severe Liver Injury. / Hata, Toshiyuki; Rehman, Fatima; Hori, Tomohide; Nguyen, Justin H.

In: Journal of Surgical Research, Vol. 236, 01.04.2019, p. 172-183.

Research output: Contribution to journalArticle

Hata, Toshiyuki ; Rehman, Fatima ; Hori, Tomohide ; Nguyen, Justin H. / GABA, γ-Aminobutyric Acid, Protects Against Severe Liver Injury. In: Journal of Surgical Research. 2019 ; Vol. 236. pp. 172-183.
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