利福平致小鼠非酒精性脂肪性肝炎作用机理研究

Study on the mechanism of rifampicin induced non-alcoholic steatohepatitis in mice

目的 利福平为一线抗结核药物,可诱导非酒精性脂肪性肝炎(NASH),但其相关作用机理有待进一步阐明。方法 幼年小鼠在出生后第二天皮下注射谷氨酸钠(monosodium glutamate, MSG)5 g/kg以诱导肥胖、胰岛素抵抗的肥胖小鼠,用于考察利福平致小鼠NASH与胰岛素抵抗的相关性;采用静脉注射氯膦酸脂质体剔除小鼠肝脏Kupffer细胞,观察Kupffer细胞在利福平致小鼠NASH中的作用。结果 MSG小鼠在50 d龄时明显肥胖,Lee’s指数显著增加,肝脏脂质轻度堆积、肝功能轻度受损,肝脏组织病理出现轻微的炎症反应。连续灌胃利福平600、300和150 mg/kg 7 d可引起正常小鼠和肥胖小鼠肝功能受损,肝脏发生NASH样病理改变,对肥胖小鼠的作用明显强于正常小鼠。注射脂质体剔除肝脏Kupffer细胞小鼠体重降低并伴随着轻微的肝损伤,但未影响肝脏中TG和TC的含量;利福平可使Kupffer细胞剔除小鼠可使其体重降低,肝脏发生NASH样改变,但与正常小鼠相比并无明显差异。结论 研究结果表明利福平所致小鼠肝脏NASH变化与胰岛素抵抗及肝脏脂质堆积程度、肝组织功能状态密切相关,这些作用与Kupffer细胞无明显关联,提示利福平在临床用于结核病治疗时应加强检测患者肝功能及脂肪肝,有利于预防利福平所致的肝损伤。

Objective Rifampicin is a first-line anti-tuberculosis drug,which can induce non-alcoholic steatohepatitis(NASH),but its mechanism remains to be further elucidated.Methods Juvenile mice were injected subcutaneously with monosodium glutamate(MSG)5 g/kg on the second day after birth to induce obese and insulin-resistant obese mice,for examining the correlation between rifampicin-induced NASH and insulin resistance.the role of Kupffer cells in rifampicin-induced NASH in mice was observed using intravenous clodronate liposome excision of mouse liver Kupffer cells.Results At the age of 50 days,MSG mice were significantly obese,with a significant increase in Lee’s index,mild accumulation of liver lipids,mildly impaired liver function,and the liver pathology showed slight inflammatory reaction.Continuous gavage of rifampicin at 600,300 and 150 mg/kg for 7 days could cause liver function damage and Nash-like pathological changes in the liver of normal and obese mice,and the effect on obese mice was significantly stronger than that in normal mice.Mice which Liposome knockout Kupffer cell decreased body weight and accompanied with mild liver injury,but did not affect the contents of TG and TC in the liver.Rifampicin could reduce body weight and NASH-like changes in the liver of Kupffer cell mice,but there was no significant difference compared with normal mice.Conclusion The results showed that the changes of liver NASH in mice caused by rifampicin were closely related to insulin resistance and the degree of hepatic lipid accumulation and functional status of liver tissues,and these effects were not significantly associated with Kupffer cells,It is suggested that rifampicin should be strengthened to detection of liver function and fatty liver when used clinically for tuberculosis treatment,which is beneficial to prevent rifampicin-induced liver injury.