Liver Failure After Extended Hepatectomy in Mice Is Mediated by a p21-Dependent Barrier to Liver Regeneration

Lehmann, Kuno; Tschuor, Christoph; Rickenbacher, Andreas; Jang, Jae–Hwi; Oberkofler, Christian E.; Tschopp, Oliver; Schultze, Simon M.; Raptis, Dimitri Aristotle; Weber, Achim; Graf, Rolf; Humar, Bostjan; Clavien, Pierre‐Alain

doi:10.1053/j.gastro.2012.08.043

Cited by 112 publications

(151 citation statements)

References 25 publications

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“…injected as an emulsion (Omegaven) 1 hour before surgery to reveal their direct effects. Examining 96 hours post 86%HX, when regeneration is most delayed, 23 Omegaven increased liver weight ( Figure 5D), consistent with a direct pro-regenerative effect on liver.…”

Section: V3fa Promote Liver Regeneration In a Direct Waysupporting

confidence: 53%

“…4,5 After 68% hepatectomy (68%HX) in lean liver, the original liver weight is gradually regained (by 50% after 48 hours, 70% after 96 hours) and completely restored after 1 week. 23 HFD-induced steatosis was associated with a delayed liver weight regain after 68%HX (45% after 48 hours, 50% after 96 hours). V3FA treatment improved regeneration patterns to those seen in lean mice (50% after 48 hours, 70% after 96 hours), suggesting that V3FA can normalize regenerative capacity ( Figure 3A).…”

Section: V3fa Accelerate the Regeneration Of Fatty Liver After Resectionmentioning

confidence: 92%

“…22 Hepatectomies (68% for normal liver regeneration, 86% for inducing liver failure) were performed as reported. 23 Omegaven (parenteral fish oil emulsion; Fresenius Kabi AG, Oberdorf, Switzerland), was intravenously (i.v.) injected 1 hour before hepatectomy at 0.2 g/kg.…”

Section: Surgical Proceduresmentioning

confidence: 99%

“…To assess cell cycle progression, we examined pH3, a differential marker for cells in the G 2 (weak nuclear positivity) and M (bold nuclear positivity) cell cycle phases. 23 The ratio of bold versus total pH3 counts thus reflects the proportion of mitotic cells among cells past the S-phase. Compared with the HFD group, V3FA-treated liver displayed a significantly increased pH3 ratio at 72 and 96 hours postresection ( Figure 3C).…”

Section: V3fa Accelerate the Regeneration Of Fatty Liver After Resectionmentioning

confidence: 99%

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Omega-3 Fatty Acids Protect Fatty and Lean Mouse Livers After Major Hepatectomy

et al. 2017

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Objective: The aim of this study was to assess the effect of V3 fatty acids (V3FA) on fatty and lean liver in hepatic surgery. Background: The global spread of energy-dense diets has led to an endemic rise in fatty liver disease and obesity. Besides metabolic pathologies, steatosis enhances hepatic sensitivity to ischemia reperfusion (I/R) and impedes liver regeneration (LR). Steatosis limits the application of liver surgery, still the main curative option for liver cancer. V3FA are known to reverse steatosis, but how these lipids affect key factors defining surgical outcomes-that is, I/R, LR, and liver malignancy-is less clear. Methods: We established a standardized mouse model of high fat diet (HFD)-induced steatosis followed by V3FA treatment and the subsequent assessment of V3FA effects on I/R, LR, and liver malignancy (n ¼ 5/group), the latter through a syngeneic metastasis approach. Fatty liver outcomes were compared with lean liver to assess steatosis-independent effects. Nonparametric statistics were applied. Results: V3FA reversed HFD-induced steatosis and markedly protected against I/R, improved LR, and prolonged survival of tumor-laden mice. Remarkably, these beneficial effects were also observed in lean liver, albeit at a smaller scale. Notably, mice with metastases in fatty versus lean livers were associated with improved survival. Conclusions: V3FA revealed multiple beneficial effects in fatty and lean livers in mice. The improvements in I/R injury, regenerative capacity, and oncological outcomes await confirmatory studies in humans.

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Section: V3fa Promote Liver Regeneration In a Direct Waysupporting

confidence: 53%

Section: V3fa Accelerate the Regeneration Of Fatty Liver After Resectionmentioning

confidence: 92%

Section: Surgical Proceduresmentioning

confidence: 99%

Section: V3fa Accelerate the Regeneration Of Fatty Liver After Resectionmentioning

confidence: 99%

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Omega-3 Fatty Acids Protect Fatty and Lean Mouse Livers After Major Hepatectomy

et al. 2017

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“…They also expose p21 as a key culprit in defective LR of HET mice. Transient p21-mediated blockade of cell cycle was also suggested as 'the' pathogenic effector of defective LR after extended hepatectomy (86%) 39 and in fatty livers. 29 This infers that heterozygous A20 KO transforms the molecular signature of a benign PH to that of either an extended hepatectomy or of a PH on a marginal fatty liver, plaguing it with equally as high lethality.…”

Section: Discussionmentioning

confidence: 99%

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

et al. 2015

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Hepatic expression of A20, including in hepatocytes, increases in response to injury, inflammation and resection. This increase likely serves a hepatoprotective purpose. The characteristic unfettered liver inflammation and necrosis in A20 knockout mice established physiologic upregulation of A20 as integral to the anti-inflammatory and anti-apoptotic armamentarium of hepatocytes. However, the implication of physiologic upregulation of A20 in modulating hepatocytes' proliferative responses following liver resection remains controversial. To resolve the impact of A20 on hepatocyte proliferation and the liver's regenerative capacity, we examined whether decreased A20 expression, as in A20 heterozygous knockout mice, affects outcome following two-third partial hepatectomy. A20 heterozygous mice do not demonstrate a striking liver phenotype, indicating that their A20 expression levels are still sufficient to contain inflammation and cell death at baseline. However, usually benign partial hepatectomy provoked a staggering lethality (440%) in these mice, uncovering an unsuspected phenotype. Heightened lethality in A20 heterozygous mice following partial hepatectomy resulted from impaired hepatocyte proliferation due to heightened levels of cyclin-dependent kinase inhibitor, p21, and deficient upregulation of cyclins D1, E and A, in the context of worsened liver steatosis. A20 heterozygous knockout minimally affected baseline liver transcriptome, mostly circadian rhythm genes. Nevertheless, this caused differential expression of 41000 genes post hepatectomy, hindering lipid metabolism, bile acid biosynthesis, insulin signaling and cell cycle, all critical cellular processes for liver regeneration. These results demonstrate that mere reduction of A20 levels causes worse outcome post hepatectomy than full knockout of bona fide liver pro-regenerative players such as IL-6, clearly ascertaining A20's primordial role in enabling liver regeneration. Clinical implications of these data are of utmost importance as they caution safety of extensive hepatectomy for donation or tumor in carriers of A20/TNFAIP3 single nucleotide polymorphisms alleles that decrease A20 expression or function, and prompt the development of A20-based liver proregenerative therapies. Humans and mice restore their liver mass within 2 weeks of surgical, viral or toxic parenchymal loss via compensatory regrowth, referred to as liver regeneration (LR). 1,2 Adequate LR is contingent upon maintaining a minimum healthy residual liver mass without which hepatocyte proliferation is stunned, resulting in hepatic failure. In liver transplantation (mainly living donor liver transplantation), 'small-for-size' syndrome illustrates this outcome. 3 Incremental 78% and 87% hepatectomy in mice reproduces this syndrome, causing 50% and 100% lethality, respectively. 4 Despite considerable knowledge characterizing the molecular basis of LR, better understanding of this process's shortcomings in the face of extensive resection and/or damage is required for uncovering therapie...

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Metabolic regulation of liver regeneration

Huang¹,

Rudnick²

2015

Signaling Pathways in Liver Diseases

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Liver Failure After Extended Hepatectomy in Mice Is Mediated by a p21-Dependent Barrier to Liver Regeneration

Cited by 112 publications

References 25 publications

Omega-3 Fatty Acids Protect Fatty and Lean Mouse Livers After Major Hepatectomy

Omega-3 Fatty Acids Protect Fatty and Lean Mouse Livers After Major Hepatectomy

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

Metabolic regulation of liver regeneration

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