Betulinic acid and betulin ameliorate acute ethanol-induced fatty liver via TLR4 and STAT3 in vivo and in vitro.
Betulinic acid and betulin ameliorate acute ethanol-induced fatty liver via TLR4 and STAT3 in vivo and in vitro.
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DOI：
10.1016/j.intimp.2013.06.012
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发表时间：
2013-10
影响因子：
5.6
通讯作者：
Ying Wan;Shuang Jiang;Li-Hua Lian;Ting Bai;Peng-He Cui;Xiao-Ting Sun;Xuejun Jin;Yan-ling Wu;Ji-Xing Nan
中科院分区：
文献类型：
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作者：
Ying Wan;Shuang Jiang;Li-Hua Lian;Ting Bai;Peng-He Cui;Xiao-Ting Sun;Xuejun Jin;Yan-ling Wu;Ji-Xing Nan
乙醇摄入导致多种肝损伤并抑制先天免疫，但其分子机制尚未完全阐明。本研究旨在探讨桦木酸（BA）和桦木醇（BT）对酒精诱导的小鼠急性脂肪肝的改善作用，以及Toll样受体4（TLR 4）和信号转导和转录激活因子3（STAT 3）在酒精诱导的肝星状细胞（HSC）中的作用。体内应用EtOH（5 mg/kg）和BA或BT（20或50 mg/kg），体外应用EtOH（50 mM）和BA或BT（12.5或25 μM）。BA或BT能显著抑制乙醇引起的血清ALT、AST和TG升高。肝脏组织病理学研究表明，BA或BT的补充可防止乙醇诱导的嗜酸性坏死，肝细胞核增加和间质炎症浸润。BA或BT可显著降低乙醇引起的CYP 2 E1活性和SREBP-1c表达，但低剂量BA或BT对CYP 2 E1活性和SREBP-1c表达的影响较小。BA或BT可显著降低酒精刺激的HSC中TLR 4的表达，增加STAT 3的磷酸化水平。BA或BT可通过调节TLR 4和STAT 3的表达，降低酒精刺激的HSC中α-SMA和I型胶原的表达，体内实验结果与此一致。所有这些发现都表明BA或BT可以通过体内和体外TLR 4和STAT 3改善急性乙醇诱导的脂肪肝，是乙醇诱导的脂肪肝治疗的有前途的药物。
Ethanol consumption leads to many kinds of liver injury and suppresses innate immunity, but the molecular mechanisms have not been fully delineated. The present study was conducted to determine whether betulinic acid (BA) or betulin (BT) would ameliorate acute ethanol-induced fatty liver in mice, and to characterize whether Toll like receptor 4 (TLR4) and signal transducer and activator of transcription 3 (STAT3) were involved in ethanol-stimulated hepatic stellate cells (HSCs). EtOH (5 mg/kg) and BA or BT (20 or 50 mg/kg) were appliedin vivo, while EtOH (50 mM) and BA or BT (12.5 or 25 μM) were appliedin vitro. Administration of BA or BT significantly prevented the increases of serum ALT and AST caused by ethanol, as well as serum TG. Supplement of BA or BT prevented ethanol-induced acidophilic necrosis, increased hepatocyte nuclei and stromal inflammation infiltration as indicated by liver histopathological studies. Administration of BA or BT significantly decreased CYP2E1 activities and expression of SREBP-1caused by ethanol, however, lower dosage of BA or BT showed slight effects on CYP2E1 activity or expression of SREBP-1c. BA or BT administration significantly decreased the expression of TLR4, and increased the phosphorylation of STAT3.In vitro, BA or BT treatment reduced the expressions of α-SMA and collagen-I in ethanol-stimulated HSCsviaregulation of TLR4 and STAT3, coincided within vivo. All of these findings demonstrated that BA or BT might ameliorate acute ethanol-induced fatty liverviaTLR4 and STAT3in vivoandin vitro, promising agents for ethanol-induced fatty liver therapies.