Mitochondrial function after associating liver partition and portal vein ligation for staged hepatectomy in an experimental model

Abstract

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 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. 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‐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) μm2; P = 0·034). Conclusion Impaired mitochondrial function and biogenesis, along with the rapid energy‐demanding cell proliferation, may cause hepatocyte dysfunction after ALPPS. 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.

Mitochondrial dysfunction attenuates rapid regeneration in livers with toxin-induced fibrosis

“…Although preliminary studies have shown that mitochondrial function, hypoxia signals, and the pathways above are involved in ALPPS-induced regeneration, there is a lack of robust evidence to support the causality (7)(8)(9)(10)15). A deeper understanding of the activation of HSCs and the JNK1/IHH axis has been demonstrated as the first example of an ALPPS-induced molecular event associated with unprecedented regenerative acceleration (7,16).…”

“…The Indian Hedgehog (IHH) pathway, mitochondrial function, and the transcriptional landscape during ALPPSinduced regeneration have been previously illustrated (7)(8)(9)(10). However, attenuation of regeneration in livers with fibrosis during ALPPS has not been well documented.…”

“…Growing evidence has shown that mitochondrial dysfunction, namely mitochondrial morphological changes, mitochondrial membrane potential, structural damage, mitochondrial DNA damage, reactive oxidative species production, will attenuate regeneration livers with fibrosis (14). Furthermore, a previous study demonstrated that impaired mitochondrial function and biogenesis, along with the rapid energy-demanding cell proliferation, could cause hepatocyte dysfunction after ALPPS (9).…”

Mild hypothermia during the reperfusion phase protects mitochondrial bioenergetics against ischemia-reperfusion injury in an animal model of ex-vivo liver transplantation—an experimental study

“…Functional evaluations of mitochondrial activity in rodents have demonstrated that, like human beings, I/R clearly affects mitochondrial function, which has implications for bioenergetics, and translates into lower energy production efficiency 32, 33. This ATP deficiency is sufficient to trigger changes in cellular metabolism; therefore, I/R injury in liver transplants interferes with the cellular bioenergetic balance.…”

Correspondence

“…In a very interesting study in a rodent model, Budai et al . found that, compared with portal vein ligation, associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is associated with pronounced bioenergetic derangement and decreased expression of peroxisome proliferator‐activated receptor γ co‐activator 1‐α (PGC1‐α), a key regulator mitochondrial biogenesis.…”