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Magnesium Isoglycyrrhizinate Ameliorates Fibrosis and Disrupts TGF-?-Mediated
SMAD Pathway in Activated Hepatic Stellate Cell Line LX2
#MMPMID30319402
Tee JK
; Peng F
; Tan YL
; Yu B
; Ho HK
Front Pharmacol
2018[]; 9
(?): 1018
PMID30319402
show ga
Liver fibrosis is a histological change often attributed to the activation of
hepatic stellate cells (HSCs) and the excessive formation of scar tissues in the
liver. Advanced stages of the disease frequently lead to cirrhosis. Magnesium
isoglycyrrhizinate (MgIG) has been accepted as a hepatoprotective drug with the
potential of alleviating inflammatory conditions and thus promote liver recovery
from viral- or drug-induced injury. While MgIG has been empirically integrated
into the clinics to treat some liver diseases, its anti-fibrotic effect and the
associated mechanisms remain poorly characterized. Herein, we demonstrated that 1
mg/ml MgIG attenuated the production of ?SMA and collagen-1 in activated HSCs
using TGF-?1-induced human HSCs LX2 as the fibrotic cell model. We found that
MgIG exerts an inhibitory effect on the TGF-?-SMAD signaling pathway by arresting
the binding of downstream transcription factors SMAD2/3 and SMAD4. Furthermore,
MgIG was shown to suppress proliferation and induce senescence of activated LX2
cells. Protein expression of p27 and enzymatic activity of senescence-associated
?-galactosidase were elevated upon exposure to MgIG. In addition, we observed
that exposure of activated LX2 cells to MgIG reduces TGF-?-induced apoptosis.
Interestingly, a lower toxicity profile was observed when human fetal hepatocytes
LO2 were exposed to the same concentration and duration of the drug, suggesting
the specificity of MgIG effect toward activated HSCs. Overall, hepatoprotective
concentrations of MgIG is shown to exert a direct effect on liver fibrosis
through inhibiting TGF-?-signaling, in which SMAD2/3 pathway could be one of the
mechanisms responsible for the fibrotic response, thereby restoring the surviving
cells toward a more quiescent phenotype. This provides critical mechanistic
insights to support an otherwise empirical therapy.
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