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

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 days, 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 to 5 hours 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 minutes before ALF induction. Results: We found that GABA-treated mice had substantial attenuation of TUNEL-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.

Revealing the Hypoglycemic Effects and Mechanism of GABA-Rich Germinated Adzuki Beans on T2DM Mice by Untargeted Serum Metabolomics

“…Interestingly, the administration of a high-dose of GABA-enriched germinated adzuki bean to the mice in group TF3 remarkably reduced the TC and TG levels ( p < 0.05, Figures 3A,B ), while the serum levels of ALT, AST, TP, and TB also showed gradually declining trends ( Figures 3C–F ), indicating that the diet administered to the TF3 group had a great protective effect on the liver of the diabetic mice, which may be attributed to a large increase in GABA content in the germinated adzuki beans. Previous studies have confirmed that GABA has anti-diabetic effects, which are mainly achieved by inhibiting obesity-related inflammation and upregulating Treg responses in vivo ( 32 ), and it was recently shown that GABA intervention can effectively protect mice from acute liver injury via GABA-mediated STAT3 signaling ( 33 ). Additionally, in all HFD + STZ-treated T2DM mice, the blood urea and serum creatinine levels decreased in a dose-dependent manner with different dosages of GABA-enriched germinated adzuki bean treatment for 6 weeks ( Figures 3G,H ), which might be associated with reduced serum lipid profiles.…”

Hepatocyte nuclear factor 4a and glucocorticoid receptor coordinately regulate lipid metabolism in mice fed a high-fat-high-sugar diet

“…4-aminobutyrate aminotransferase (ABAT), a key enzyme for GABA catabolism and mitochondrial nucleoside metabolism (9), tended to be gene-dosage-dependently decreased in the heterozygote and knockout mice (↓94%). Interestingly, GABA potently protects against severe liver injury (46). Thus, the dramatic down-regulation of ABAT in the knockout mice may impair mitochondrial nucleoside metabolism but protect the knockout mice from liver injury via elevated GABA.…”

Listeria monocytogenes infection rewires host metabolism with regulatory input from type I interferons

“…This hypothesis is supported by increased GABA in Ifnar1 -/- livers and by the slightly increased OXPHOS dependency of Ifnar1 -/- macrophages on glutaminolysis compared to wt. Of note, recent reports attribute a protective effect to GABA in both acute liver injury [ 36 ] and L . monocytogenes infection [ 37 ], although involvement of IFN-I signaling has not been addressed in the latter study.…”