Beta-Catenin Activation Promotes Liver Regeneration after Acetaminophen-Induced Injury

Apte, Udayan; Singh, Sucha; Zeng, Gang; Cieply, Benjamin; Virji, Mohamed A.; Wu, Tong; Monga, Satdarshan P.

doi:10.2353/ajpath.2009.080976

Cited by 144 publications

(142 citation statements)

References 42 publications

(56 reference statements)

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“…Previous studies have identified that ␤-catenin is activated early on in regeneration in response to PH and acetaminopheninduced toxic liver injury (2,50). Hepatocyte-specific deletion of ␤-catenin results in delayed hepatocyte proliferation in response to PH (61,66).…”

Section: Discussionmentioning

confidence: 99%

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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%

“…Activation and nuclear translocation of ␤-catenin is an early event in response to PH and toxic liver injury (2,50). Activated ␤-catenin is a known mediator of cyclin D1 expression and hepatocyte proliferation in regenerating livers.…”

Section: Immediate Early Genes Egr-1 and Ap-1 Dna-binding Activity Ismentioning

confidence: 99%

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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“…Recently, Niva et al [23] found that E. japonensis GS may play role in regeneration, which is consistent with our result. By performing a dose response study, where CD1-mice injected with non-lethal or lethal doses of acetaminophen, Apte et al [24] identified that b-catenin activation is related to increased liver regeneration and that a positive role of b-catenin in impelling regeneration following toxicant-induced liver failure by mediating proliferation through regulation of cyclin-D1 levels. They noticed that b-catenin activation is an early event and is vital for regeneration.…”

Section: Discussionmentioning

confidence: 99%

Expression level of glutamine synthetase is increased in hepatocellular carcinoma and liver tissue with cirrhosis and chronic hepatitis B

et al. 2010

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Studies have suggested that glutamine synthetase (GS) is a potential marker of hepatocellular carcinoma (HCC). We aimed to evaluate the expression of GS in non-malignant liver tissue and serum GS levels in HCC, liver cirrhosis (LC), chronic hepatitis B (CHB), five kinds of extrahepatic diseases patients and healthy subjects. Immunohistochemistry (IHC) was used to assess GS expression in 260 liver tissue samples (from 120 HCC, 90 CHB stage 4, and 50 CHB stage 1-3 patients). Enzymelinked immunosorbent assays of 325 samples (from 100 healthy donors, 33 CHB stage 1-3, 43 CHB stage 4, 111 HCC, and 45 extrahepatic diseases patients) were used to further analyze GS levels in serum. IHC studies showed the expression of GS in 70% of HCC patients, 46.7% of CHB stage 4 patients and 38% of CHB stage 1-3 patients. The v 2 tests showed significant difference between HCC samples and non-tumor tissues (P = 0.001 for HCC vs. CHB stage 4, P = 0.000 for HCC vs. CHB). Consistent with this, serum GS levels are increased in HCC and CHB stage 1-4 patients. There are significant differences among all samples (P = 0.000 for all), except CHB stage 1-3 versus CHB stage 4 (P = 0.552). Based on multiple linear regressions, HCC, CHB stage 1-4 and AFP were significantly associated with serum GS levels. In addition, in HCC group, TNM and Child-Pugh were significantly associated with GS levels. Expression of GS is increased in HCC, LC, and CHB. It may be a new serum marker for liver disease.Keywords Glutamine synthetase Á Hepatocellular carcinoma Á Liver cirrhosis Á Chronic hepatitis B Á Regeneration Á Receiver operating characteristic curve Á Sensitivity and specificity Abbreviations

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“…To quantify Wnt and frizzled (Fzl) mRNA levels, TaqMan-based real-time polymerase chain reaction (PCR) arrays (Applied Biosystems, Foster City, CA) were used. Total RNA was isolated from the livers of 8-and 14-month-old WT and FXR-KO mice using the TRIzol method according to the manufacturer's protocol (Sigma-Aldrich, St. Louis, MO) and converted to cDNA as described previously (Apte et al, 2009). Realtime PCR was performed on a StepOnePlus real-time PCR machine (Applied Biosystems).…”

Section: Methodsmentioning

confidence: 99%

Increased Activation of the Wnt/β-Catenin Pathway in Spontaneous Hepatocellular Carcinoma Observed in Farnesoid X Receptor Knockout Mice

Wolfe

Thomas²,

Edwards³

et al. 2011

J Pharmacol Exp Ther

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Farnesoid X receptor (FXR), the primary bile acid-sensing nuclear receptor, also is known for its anticancer properties. It is known that FXR deficiency in mice results in spontaneous hepatocellular carcinoma (HCC), but the mechanisms are not completely understood. We report that sustained activation of the Wnt/␤-catenin pathway is associated with spontaneous HCC in FXR-knockout (KO) mice. HCC development was studied in FXR-KO mice at 3, 8, and 14 months of age. No tumors were observed at either 3 or 8 months, but the presence of HCC was observed in 100% of the FXR-KO mice at the age of 14 months. Further analysis revealed no change in ␤-catenin activation in the livers of 3-month-old FXR-KO mice, but a moderate increase was observed in 8-month-old FXR-KO mice. ␤-Catenin activation further increased significantly in 14-month-old tumor-bearing mice. Further analysis revealed that two independent mechanisms might be involved in ␤-catenin activation in the livers of FXR-KO mice. Activation of canonical Wnt signaling was evident as indicated by increased Wnt4 and dishevelled expression along with glycogen synthase kinase-3␤ inactivation. We also observed decreased expression of E-cadherin, a known regulator of ␤-catenin, in FXR-KO mice. The decrease in E-cadherin expression was accompanied by increased expression of its transcriptional repressor, Snail. Consistent with the increased HCC in FXR-KO mice, we observed a significant decrease in FXR expression and activity in human HCC samples. Taken together, these data indicate that a temporal increase in the activation of Wnt/␤-catenin is observed during spontaneous HCC development in FXR-KO mice and is potentially critical for tumor development.

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Beta-Catenin Activation Promotes Liver Regeneration after Acetaminophen-Induced Injury

Cited by 144 publications

References 42 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

Expression level of glutamine synthetase is increased in hepatocellular carcinoma and liver tissue with cirrhosis and chronic hepatitis B

Increased Activation of the Wnt/β-Catenin Pathway in Spontaneous Hepatocellular Carcinoma Observed in Farnesoid X Receptor Knockout Mice

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