Mitochondrial function after associating liver partition and portal vein ligation for staged hepatectomy in an experimental model
Mitochondrial function after associating liver partition and portal vein ligation for staged hepatectomy in an experimental model
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DOI：
10.1002/bjs.10978
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发表时间：
2019-01-01
影响因子：
9.6
通讯作者：
Fulop, A.
中科院分区：
文献类型：
--
作者：
Budai, A.;Horvath, G.;Fulop, A.
背景资料：联合肝脏分割和门静脉结扎进行分期肝切除术（ALPPS）是一种诱导残肝快速再生的两阶段策略。该技术与高死亡率和发病率相关。本研究旨在评估ALPPS诱导的肝再生过程中线粒体的功能，生物发生和形态学。方法：雄性Wistar大鼠（n = 100）进行门静脉结扎（PVL）或ALPPS。分别于干预后0 h（不手术）、24、48、72和168 h处死动物。再生率和增殖指数进行了评估。测定线粒体耗氧量和5 '-三磷酸腺苷（ATP）的产生。通过过氧化物酶体增殖物激活受体γ共激活因子（PGC）1-α、核呼吸因子（NRF）1和2以及线粒体转录因子γ的蛋白质水平测量来评价线粒体生物发生。结果：与PVL组相比，ALPPS组的再生率和Ki-67指数显著升高（168 h再生率：平均值（s.d.）291.2（21.4）对比245.1（13.8）%，P < 0.001; 24 h Ki-67指数：86.9（4.6）对比66.2（4.9）%，P < 0.001）。与PVL组相比，ALPPS组在干预后48 h线粒体功能受损（诱导ATP生成）;（复合物I：361.9（72.3）vs 629.7（165.8）nmol/min/mg，P= 0.038;复合物II：517.5（48.8）对794.8（170.4）nmol/min/mg，P = 0.044）。与PVL相比，ALPPS后48和72 h的线粒体生物发生标志物显著降低（48 h的PGC 1-α：降低0.61倍，P = 0.045; 48 h的NRF 1：降低0.48倍，P = 0.028）。ALPPS后肝细胞线粒体体积明显减小（0.26（0.05）vs.0.40（0.07）μ m（2）; P = 0.034）。结论：ALPPS后肝细胞线粒体功能和生物合成受损，沿着细胞快速增殖，可能导致肝细胞功能障碍。
Background: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a two-stage strategy to induce rapid regeneration of the remnant liver. The technique has been associated with high mortality and morbidity rates. This study aimed to evaluate mitochondrial function, biogenesis and morphology during ALPPS-induced liver regeneration.Methods: Male Wistar rats (n = 100) underwent portal vein ligation (PVL) or ALPPS. The animals were killed at 0 h (without operation), and 24, 48, 72 or 168 h after intervention. Regeneration rate and proliferation index were assessed. Mitochondrial oxygen consumption and adenosine 5'-triphosphate (ATP) production were measured. Mitochondrial biogenesis was evaluated by protein level measurements of peroxisome proliferator-activated receptor gamma co-activator (PGC) 1-alpha, nuclear respiratory factor (NRF) 1 and 2, and mitochondrial transcription factor gamma. Mitochondrial morphology was evaluated by electron microscopy.Results: Regeneration rate and Ki-67 index were significantly raised in the ALPPS group compared with the PVL group (regeneration rate at 168 h: mean(s.d.) 291.2(21.4) versus 245.1(13.8) per cent, P < 0.001; Ki-67 index at 24 h: 86.9(4.6) versus 66.2(4.9) per cent, P < 0.001). In the ALPPS group, mitochondrial function was impaired 48 h after the intervention compared with that in the PVL group (induced ATP production); (complex I: 361.9(72.3) versus 629.7(165.8) nmol per min per mg, P= 0.038; complex II: 517.5(48.8) versus 794.8(170.4) nmol per min per mg, P = 0.044). Markers of mitochondrial biogenesis were significantly lower 48 and 72 h after ALPPS compared with PVL (PGC1-alpha at 48 h: 0.61-fold decrease, P = 0.045; NRF1 at 48 h: 0.48-fold decrease, P = 0.028). Mitochondrial size decreased significantly after ALPPS (0.26(0.05) versus 0.40(0.07) mu m(2); P = 0.034).Conclusion: Impaired mitochondrial function and biogenesis, along with the rapid energy-demanding cell proliferation, may cause hepatocyte dysfunction after ALPPS.