Background
Nonalcoholic steatohepatitis (NASH) is one of the main chronic liver diseases. NASH is identified by lipid accumulation, inflammation, and fibrosis. Jinan Red Ginseng (JRG) and licorice have been widely used because of their anti-inflammatory and hepatoprotective effects. Hence, this study assessed JRG and licorice extract mixtures' effects on NASH progression.
Methods
Palmitic acid (PA) and the western diet (WD) plus, high glucose-fructose water were used to induce
in vitro
and
in vivo
NASH. Mice were orally administered with JRG-single (JRG-S) and JRG-mixtures (JRG-M; JRG-S + licorice) at 0, 50, 100, 200 or 400 mg/kg/day once a day during the last half-period of diet feeding.
Results
JRG-S and JRG-M reduced NASH-related pathologies in WD-fed mice. JRG-S and JRG-M consistently decreased the mRNA level of genes related with inflammation, fibrosis, and lipid metabolism. The treatment of JRG-S and JRG-M also diminished the SREBP-1c protein levels and the p-AMPK/AMPK ratio. The FAS protein levels were decreased by JRG-M treatment both
in vivo
and
in vitro
but not JRG-S.
Conclusion
JRG-M effectively reduced lipogenesis by modulating AMPK downstream signaling. Our findings suggest that this mixture can be used as a prophylactic or therapeutic alternative for the remedy of NASH.
Nonalcoholic steatohepatitis (NASH) is one of the most common liver diseases and a major cause of liver fibrosis worldwide. Γ-Aminobutyric acid (GABA) is one of the most abundant inhibitory neurotransmitters in the central nervous system. Recently, it has been reported that GABAergic signaling pathways are found in various non-neuronal tissues including the immune system and play a functional role. In the present study, we investigated whether administration of GABA has effects on NASH through its immunomodulatory effects. To test this hypothesis, C57BL/6 mice were fed a methionine–choline-deficient (MCD) diet for 8 weeks. After four weeks into MCD feeding, mice were provided with plain water (control) or water containing 2 mg/mL of GABA for the subsequent 4 weeks. Using this MCD diet-induced NASH model, we found that mice receiving GABA showed more severe steatohepatitis and liver fibrosis than control mice. This increased liver damage was confirmed by higher levels of serum alanine transaminase (ALT) and aspartate aminotransferase (AST) compared to the control group. In accordance with increased liver steatohepatitis, NASH-related and inflammatory gene expression (collagen α1, tissue inhibitor of metalloproteinase-1, TNF-α) in the liver was markedly increased in GABA-treated mice. Furthermore, GABA directly enhanced production of inflammatory cytokines including IL-6 and TNF-α in LPS activated RAW macrophage cells and increased TIB–73 hepatocyte death. Such effects were abolished when GABA was treated with bicuculline, a competitive antagonist of GABA receptors. These results suggest that oral administration of GABA may be involved in changes of the liver immune milieu and conferred detrimental effects on NASH progression.
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