First Department of Surgery, Hepato-Pancreato-Biliary Surgical Research Centre, Budapest, Hungary.
Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary.
Br J Surg. 2019 Jan;106(1):120-131. doi: 10.1002/bjs.10978. Epub 2018 Sep 27.
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.
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 γ co-activator (PGC) 1-α, nuclear respiratory factor (NRF) 1 and 2, and mitochondrial transcription factor α. Mitochondrial morphology was evaluated by electron microscopy.
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-α 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) μm ; P = 0·034).
Impaired mitochondrial function and biogenesis, along with the rapid energy-demanding cell proliferation, may cause hepatocyte dysfunction after ALPPS. Surgical relevance Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a well known surgical strategy that combines liver partition and portal vein ligation. This method induces immense regeneration in the future liver remnant. The rapid volume increase is of benefit for resectability, but the mortality and morbidity rates of ALPPS are strikingly high. Moreover, lagging functional recovery of the remnant liver has been reported recently. In this translational study, ALPPS caused an overwhelming inflammatory response that interfered with the peroxisome proliferator-activated receptor γ co-activator 1-α-coordinated, stress-induced, mitochondrial biogenesis pathway. This resulted in the accumulation of immature and malfunctioning mitochondria in hepatocytes during the early phase of liver regeneration (bioenergetic destabilization). These findings might explain some of the high morbidity if confirmed in patients.
联合肝脏分隔和门静脉结扎的分步肝切除术（ALPPS）是一种诱导残余肝脏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 诱导肝再生过程中的线粒体功能、生物发生和形态。
雄性 Wistar 大鼠（n=100）行门静脉结扎（PVL）或 ALPPS。动物在干预后 0 h（无手术）和 24、48、72 或 168 h 时被处死。评估再生率和增殖指数。测量线粒体耗氧量和三磷酸腺苷（ATP）生成。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α的蛋白水平测量评估线粒体生物发生。通过电子显微镜评估线粒体形态。
与 PVL 组相比，ALPPS 组的再生率和 Ki-67 指数显著升高（168 h 时的再生率：平均（标准差）291·2（21·4）%比 245·1（13·8）%，P<0·001；24 h 时的 Ki-67 指数：86·9（4·6）%比 66·2（4·9）%，P<0·001）。与 PVL 组相比，ALPPS 组在干预后 48 h 时线粒体功能受损（诱导 ATP 生成）（复合物 I：361·9（72·3）比 629·7（165·8）nmol/min/mg，P=0·038；复合物 II：517·5（48·8）比 794·8（170·4）nmol/min/mg，P=0·044）。与 PVL 相比，ALPPS 后 48 和 72 h 时线粒体生物发生标志物明显降低（PGC1-α在 48 h 时：0·61 倍下降，P=0·045；NRF1 在 48 h 时：0·48 倍下降，P=0·028）。线粒体大小在 ALPPS 后明显减小（0·26（0·05）比 0·40（0·07）μm；P=0·034）。
在 ALPPS 后，线粒体功能和生物发生受损，伴随着快速的能量需求细胞增殖，可能导致肝细胞功能障碍。手术相关性联合肝脏分隔和门静脉结扎的分步肝切除术（ALPPS）是一种众所周知的手术策略，它结合了肝脏分隔和门静脉结扎。这种方法可以使未来的肝残存量迅速增加。体积的快速增加有利于可切除性，但 ALPPS 的死亡率和发病率非常高。此外，最近有报道称残留肝脏的功能恢复滞后。在这项转化研究中，ALPPS 引起了强烈的炎症反应，干扰了过氧化物酶体增殖物激活受体 γ 共激活因子 1-α 协调的、应激诱导的、线粒体生物发生途径。这导致在肝再生的早期阶段（生物能量不稳定），肝细胞中积累不成熟和功能失调的线粒体。如果在患者中得到证实，这些发现可能解释了一些高发病率的原因。
