Adenine nucleotide changes in the remnant liver: An early signal for regeneration after partial hepatectomy

Crumm, Sara; Cofán, Montserrat; Juskeviciute, Egle; Hoek, Jan B.

doi:10.1002/hep.22421

Cited by 66 publications

(63 citation statements)

References 56 publications

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“…Discrete release of nucleotides in response to a variety of cellular stresses including shear stress has been observed in many cell types (12). Studies by Crumm et al (14), focusing on very early time points (minutes) after PH, suggest that rapid release of ATP generates early stress signals that contribute to the onset of liver regeneration. Recent studies focusing on extracellular ATP phosphohydrolysis further highlight the importance of extracellular nucleotides as key regulators of liver regeneration (6,8,27).…”

Section: Discussionmentioning

confidence: 99%

“…Our studies in rats infused with P2 purinergic receptor antagonist PPADS prior to 70% PH suggested a role for extracellular ATP-mediated P2 purinergic receptor activation in regenerating livers (67). Recent studies have provided evidence for the rapid release of adenine nucleotides in response to PH and for the requirement of CD39/ENTPD1-mediated catalysis of extracellular nucleotides for efficient liver regeneration (6,14,25,27). These studies highlight the importance of extracellular ATP-mediated purinergic signaling in liver regeneration.…”

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confidence: 97%

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P2Y2 purinergic receptor activation is essential for efficient hepatocyte proliferation in response to partial hepatectomy

Tackett

Sun

Mei

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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cellular nucleotides via activation of P2 purinergic receptors influence hepatocyte proliferation and liver regeneration in response to 70% partial hepatectomy (PH). Adult hepatocytes express multiple P2Y (G protein-coupled) and P2X (ligand-gated ion channels) purinergic receptor subtypes. However, the identity of key receptor subtype(s) important for efficient hepatocyte proliferation in regenerating livers remains unknown. To evaluate the impact of P2Y2 purinergic receptor-mediated signaling on hepatocyte proliferation in regenerating livers, wild-type (WT) and P2Y2 purinergic receptor knockout (P2Y2Ϫ/Ϫ) mice were subjected to 70% PH. Liver tissues were analyzed for activation of early events critical for hepatocyte priming and subsequent cell cycle progression. Our findings suggest that early activation of p42/44 ERK MAPK (5 min), early growth response-1 (Egr-1) and activator protein-1 (AP-1) DNA-binding activity (30 min), and subsequent hepatocyte proliferation (24 -72 h) in response to 70% PH were impaired in P2Y2Ϫ/Ϫ mice. Interestingly, early induction of cytokines (TNF-␣, IL-6) and cytokine-mediated signaling (NF-B, STAT-3) were intact in P2Y2Ϫ/Ϫ remnant livers, uncovering the importance of cytokine-independent and nucleotidedependent early priming events critical for subsequent hepatocyte proliferation in regenerating livers. Hepatocytes isolated from the WT and P2Y2Ϫ/Ϫ mice were treated with ATP or ATP␥S for 5-120 min and 12-24 h. Extracellular ATP alone, via activation of P2Y2 purinergic receptors, was sufficient to induce ERK phosphorylation, Egr-1 protein expression, and key cyclins and cell cycle progression of hepatocytes in vitro. Collectively, these findings highlight the functional significance of P2Y2 purinergic receptor activation for efficient hepatocyte priming and proliferation in response to PH. extracellular ATP; P2Y2 purinergic receptors; partial hepatectomy; hepatocyte proliferation; liver regeneration LIVER REGENERATION IN RESPONSE to partial hepatectomy (PH) is a highly coordinated process involving a complex interplay of multiple humoral factors and integration of cell signaling in parenchymal and nonparenchymal cells (45). In response to PH, adult hepatocytes are "reprogrammed" to undergo cell cycle progression and proliferation until tissue restitution is achieved. The factor(s) that trigger cell cycle progression of hepatocytes in response to PH as well as cellular events that play a role in the reestablishment of quiescence upon the completion of liver growth are not well understood.In response to 70% PH, the remnant livers are subjected to elevated shear stress and trigger the release of factors believed to play key roles in the initiation of proliferative response in hepatocytes (1, 15, 60). Cellular stress including shear stress is a potent trigger for ATP release. Extracellular ATP, via the activation of cell surface P2 purinergic receptors, influences cell signaling, activation of transcription factors, and gene expression (5, 18). In recent years, extracellular ATP is begin...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 97%

P2Y2 purinergic receptor activation is essential for efficient hepatocyte proliferation in response to partial hepatectomy

Tackett

Sun

Mei

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Also, cellular ATP stores have been shown to play an important role in liver regeneration, by supplying energy and regulating posttranscriptional activation of cyclin D1/cyclin-dependent kinase (cdk) complexes (31)(32)(33). To investigate whether the effect of complement inhibition on hepatoprotection and liver regeneration was associated with hepatic ATP levels, ATP concentrations were measured in liver samples from all groups at various time points after IRI and PHx.…”

Section: Figurementioning

confidence: 99%

A complement-dependent balance between hepatic ischemia/reperfusion injury and liver regeneration in mice

He¹,

Atkinson²,

Qiao³

et al. 2009

J. Clin. Invest.

125

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Massive liver resection and small-for-size liver transplantation pose a therapeutic challenge, due to increased susceptibility of the remnant/graft to ischemia reperfusion injury (IRI) and impaired regeneration. We investigated the dual role of complement in IRI versus regeneration in mice. Complement component 3 (C3) deficiency and complement inhibition with complement receptor 2-complement receptor 1-related protein y (CR2-Crry, an inhibitor of C3 activation) provided protection from hepatic IRI, and while C3 deficiency also impaired liver regeneration following partial hepatectomy (PHx), the effect of CR2-Crry in this context was dose dependent. In a combined model of IRI and PHx, either C3 deficiency or high-dose CR2-Crry resulted in steatosis, severe hepatic injury, and high mortality, whereas low-dose CR2-Crry was protective and actually increased hepatic proliferative responses relative to control mice. Reconstitution experiments revealed an important role for the C3a degradation product acylation-stimulating protein (ASP) in the balance between inflammation/injury versus regeneration. Furthermore, liver regeneration was dependent on the putative ASP receptor, C5L2. Several potential mechanisms of hepatoprotection and recovery were identified in mice treated with low-dose CR2-Crry, including enhanced IL-6 expression and STAT3 activation, reduced hepatic ATP depletion, and attenuated oxidative stress. These data indicate that a threshold of complement activation, involving ASP and C5L2, promotes liver regeneration and suggest a balance between complement-dependent injury and regeneration.

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“…Several early events associated with liver regeneration have been attributed to acute hemodynamic changes and associated shear-stress-induced release of humoral factors such as nucleotides and nitric oxide from the hepatic parenchyma. [2][3][4][5][6] Cytokinemediated and growth factor-mediated induction of cell signaling has been shown to be integral to the activation of a highly orchestrated gene expression program responsible for the stepwise reorganization of extracellular matrix, cell proliferation, and liver growth. 1 Studies based on 70% partial hepatectomy of rodents, especially in gene knockout and transgenic mice, have uncovered the functional significance of distinct signaling cascades and genes necessary for cell proliferation and survival in regenerating livers.…”

mentioning

confidence: 99%

Adipose to the rescue: Peripheral fat fuels liver regeneration

Thevananther

2010

Hepatology

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Adenine nucleotide changes in the remnant liver: An early signal for regeneration after partial hepatectomy

Cited by 66 publications

References 56 publications

P2Y2 purinergic receptor activation is essential for efficient hepatocyte proliferation in response to partial hepatectomy

P2Y2 purinergic receptor activation is essential for efficient hepatocyte proliferation in response to partial hepatectomy

A complement-dependent balance between hepatic ischemia/reperfusion injury and liver regeneration in mice

Adipose to the rescue: Peripheral fat fuels liver regeneration

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