Major role of apolipoprotein B in cycloheximide-induced acute hepatic steatosis in mice
Major role of apolipoprotein B in cycloheximide-induced acute hepatic steatosis in mice
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DOI：
10.1111/j.1872-034x.2011.00791.x
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发表时间：
2011-05-01
影响因子：
4.2
通讯作者：
Ozono, Keiichi
中科院分区：
文献类型：
--
作者：
Murakami, Mari;Bessho, Kazuhiko;Ozono, Keiichi
目的：肝脂肪变性伴蛋白质合成障碍是肝功能损害的常见表现。为了评估蛋白质合成抑制是否直接诱导肝脂肪变性，我们研究了放线菌酮（CHX）诱导的脂肪肝小鼠的分子机制。方法：C57/BL 6CR小鼠腹腔注射CHX（20 mg/kg），每4 h 3次，诱导肝脂肪变性。肝脏脂质分泌，脂肪酸氧化，肝脏脂肪生成和肝脏脂质摄取evaluated.Results：24小时后，第一CHX注射，CHX治疗小鼠的肝脏脂质水平增加到1.8倍，在控制，但在48小时内恢复正常。肝脏甘油三酯（TG）分泌率显著下降至对照组的22%，载脂蛋白B（apo B）蛋白水平下降，但微粒体TG转移蛋白未下降。对照组和CHX处理组小鼠的apob基因表达无显著差异。另一方面，血浆游离脂肪酸和脂肪生成蛋白水平未增加，血浆β-羟基丁酸水平保持稳定，表明在该模型中脂肪酸氧化、肝脏脂质摄取和脂肪生成之间的协调平衡未被破坏。CHX处理的HepG 2细胞中也观察到细胞脂质积聚和细胞和分泌的apoB减少。HepG 2细胞中apoB的敲低也导致了细胞TG的积累。结论：我们证明了由于急性apoB减少导致的肝脏脂质分泌减少参与了CHX诱导的肝脏脂肪变性的发病机制。
Aim:Hepatic steatosis accompanied by impaired protein synthesis is often observed in hepatic dysfunction. To assess whether protein synthesis inhibition directly induces hepatic steatosis, we investigated the molecular mechanisms of cycloheximide (CHX)-induced fatty liver mice.Methods:C57/BL6CR mice were i.p. administrated CHX (20 mg/kg) three times every 4 h to induce hepatic steatosis. Hepatic lipid secretion, fatty acid oxidation, hepatic lipogenesis and hepatic lipid uptake were evaluated.Results:Twenty-four hours after the first CHX injection, hepatic lipid levels increased in CHX-treated mice to 1.8-fold of that in controls but returned to normal within 48 h. The hepatic triglyceride (TG) secretion rate decreased significantly to 22% of controls, and the apolipoprotein B (apoB) protein level, but not microsomal TG transfer protein, decreased in CHX-treated mice. The apob gene expression was not significantly different between controls and CHX-treated mice. On the other hand, plasma free fatty acid and lipogenic protein levels did not increase and plasma beta-hydroxybutyrate level remained stable, suggesting that the coordinated balance between fatty acid oxidation, hepatic lipid uptake and lipogenesis was not disrupted in this model. Cellular lipid accumulation and decreased cellular and secreted apoB were also observed in CHX-treated HepG2 cells. Knockdown of apoB in HepG2 cells also resulted in the cellular TG accumulation.Conclusion:We demonstrated that decreased hepatic lipid secretion due to acute apoB reduction is involved in the pathogenesis of CHX-induced liver steatosis.