| Fibrosis is the progressive pathological process in which the body’s wound healing and tissue remodeling mechanisms respond to liver injury in all chronic hepatopath. Hepatic fibrosis is the necessary stage in the development of cirrhosis and plays an important part in liver cancer. It is the common pathological foundation in all advanced stage complications of chronic liver disease. The main cell type responsible for the development of fibrosis is the activated hepatic stellate cell (HSC). The molecule mechanism of activated hepatic stellate cells proliferate and synthesize extracellular matrix proteins to produce the fibrous scar is the research point recently. It has been suggested that the use of anti-inflammatory, anti-oxidative stress agents might be useful in preventing the activation of HSCs, consequently, in the development of liver fibrosis. HSC is the target cell that suffer from various kinds of hepatic toxic agents including hepatitis virus, alcohol metabolites and bile acid. The hepatic toxic agents destroy the hepatocyte, release reactive oxygen species (ROS) and inflammatory mediators causing that activate inflammatory cells and contributes to activate HSC to aggravate the development of liver fibrosis.This study select TAA and alcohol to make animal liver fibrosis and acute ethanol fatty liver models, research on the hepato-protective effect and the underlying mechanism of BA in vivo and in vitro.(1) Liver fibrosis was induced by intraperitoneal injections of thioacetamide (TAA,200mg/kg) twice weekly for6weeks in Wistar rats. The administration of BA (20mg/kg or50mg/kg) was started following TAA injections and was continued for6or8weeks to evaluate both the preventive and the protective effects. BA demonstrated great efficacy in preventing and curing hepatic fibrosis via attenuating the TAA-mediated increases in liver’tissue hydroxyproline and α-smooth muscle actin (a-SMA). In vitro, BA effectively decreased the HSC-T6cell viability induced by TNF-a and showed low toxicity in normal human chang liver cells. Moreover, BA significantly attenuated the expression of a-SMA and tissue inhibitor of metalloproteinase-1(TIMP-1) and increased the levels of matrix metalloprotease (MMP)-13. BA also inhibited the expression of toll-like receptor4(TLR4), myeloid differentiation factor88(MyD88) and the activation of nuclear factor-κB (NF-κB) in a time-dependent manner.(2) Mice were treated with ethanol (5g/kg, body weight) by gavage every12h for a total of3doses to induce acute fatty liver. BA and BT (50or20mg/kg) were gavaged simultaneously with ethanol for3doses. Hepatic stellate cells was activated by ethanol (50mM) for24h and simultaneous treated with BA or BT25μM and12.5μM to observe the protective effect against ethanol in vitro. BA or BT administration significantly reduced the increases in serum ALT, AST and triglyceride levels at4h after the last ethanol administration. BA and BT were also found to prevent ethanol-induced hepatic steatosis and necrosis, as indicated by liver histopathological studies. Meanwhile, both of them showed a powerful inhibitory effect on CYP2E1and SREBP-1expression. In vitro, ethanol concentrations among20-200mM exhibited hardly any effect on cell viability and treated with B A and BT did not influence the cell proliferation. Moreover, BA and BT effectively reduced the ECM accumulation via decreasing collagen-1levels and attenuating the expression of a-SMA. However, BA and BT also excellently decreased AMPK and STAT3levels that controlled SREBP-1expression in ethanol induced hepatic steatosis. The hepato-protective effect of BA and BT may be related with the inhibition of TLR4/MyD88signal pathway and the activation of NF-κB. Among that, BA showed a more powerful hepato-protective effect on ethanol induced liver steatosis.Thus, BA may be useful as a potential pharmacological therapy for the prevention of liver fibrosis and acute fatty liver. Further investigation is required to determine the exact protective mechanism and to discover the active candidates. |
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