Glycogen synthase kinase 3β-dependent Snail degradation directs hepatocyte proliferation in normal liver regeneration

Sekiya, Sayaka; Suzuki, Atsushi

doi:10.1073/pnas.1016122108

Cited by 36 publications

(34 citation statements)

References 20 publications

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“…Previous studies in mice have shown that disruption of the GSK-3β gene results in embryonic lethality because of severe mid-gestation liver degeneration [13] . The inhibition of GSK-3β also impairs the regeneration of adult rat liver after PH [15,17] . These findings suggest that GSK-3β is essential for liver development and regeneration in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…GSK-3β activity is increased by the site-specific phosphorylation of Tyr216, whereas the phosphorylation of Ser9 inhibits GSK-3β activity [12] . A growing body of research has identified a critical role of GSK-3β signaling in various aspects of hepatic biology, including liver development, regeneration, proliferation, and hepatocellular carcinoma (HCC) pathogenesis [13][14][15][16][17][18] . However, there have been relatively few reports that connect GSK-3β signaling with liver oval cells.…”

Section: Introductionmentioning

confidence: 99%

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GSK-3β suppresses the proliferation of rat hepatic oval cells through modulating Wnt/β-catenin signaling pathway

Xie

Zhong

et al. 2015

Acta Pharmacol Sin

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Aim: Glycogen synthase kinase 3β (GSK-3β) plays a crucial role in hepatic biology, including liver development, regeneration, proliferation and carcinogenesis. In this study we investigated the role of GSK-3β in regulation of growth of hepatic oval cells in vitro and in liver regeneration in partially hepatectomized rats. Methods: WB-F344 cells, the rat hepatic stem-like epithelial cells, were used as representative of oval cells. Cell viability was examined using a WST-8 assay. The cells were transfected with a recombinant lentivirus expressing siRNA against GSK-3β (GSK3βRNAiLV) or a lentivirus that overexpressed GSK-3β (GC-GSK-3βLV). Adult rats underwent partial (70%) hepatectomy, and liver weight and femur length were measured at d 7 after the surgery. The expression of GSK-3β, phospho-Ser 9 -GSK-3β, β-catenin and cyclin D1 was examined with immunoblotting assays or immunohistochemistry. Results: Treatment of WB-F344 cells with the GSK-3β inhibitor SB216763 (5 and 10 µmol/L) dose-dependently increased the levels of phospho-Ser 9 -GSK-3β, but not the levels of total GSK-3β, and promoted the cell proliferation. Knockout of GSK-3β with GSK-3βRNAiLV increased the cell proliferation, whereas overexpression of GSK-3β with GC-GSK-3βLV decreased the proliferation. Both SB216763 and GSK-3βRNAiLV significantly increased the levels of β-catenin and cyclin D1 in the cells, whereas GSK-3β overexpression decreased their levels. In rats with a partial hepatectomy, administration of SB216763 (2 mg/kg, ip) significantly increased the number of oval cells, the levels of phospho-Ser 9 -GSK-3β, β-catenin and cyclin D1 in liver, as well as the ratio of liver weight to femur length at d 7 after the surgery. Conclusion: GSK-3β suppresses the proliferation of hepatic oval cells by modulating the Wnt/β-catenin signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

GSK-3β suppresses the proliferation of rat hepatic oval cells through modulating Wnt/β-catenin signaling pathway

Xie

Zhong

et al. 2015

Acta Pharmacol Sin

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“…However, ERK1/2 may become inactivated in elder mice and result in decreasing hepatocyte proliferation. Given the close relationship between cell proliferation and lipid metabolism (43,44), changes in proliferation resulting from manipulation of ERK1/2 activity may also influence the lipid accumulation in db/db or HFD mice.…”

Section: Discussionmentioning

confidence: 99%

Activation of ERK1/2 Ameliorates Liver Steatosis in Leptin Receptor–Deficient (db/db) Mice via Stimulating ATG7-Dependent Autophagy

Xiao

Liu

et al. 2015

Diabetes

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Although numerous functions of extracellular signalregulated kinase 1/2 (ERK1/2) are identified, a direct effect of ERK1/2 on liver steatosis has not been reported. Here, we show that ERK1/2 activity is compromised in livers of leptin receptor-deficient (db/db) mice. Adenovirusmediated activation of mitogen-activated protein kinase kinase 1 (MEK1), the upstream regulator of ERK1/2, significantly ameliorated liver steatosis in db/db mice, increased expression of genes related to fatty acid b-oxidation and triglyceride (TG) export and increased serum b-hydroxybutyrate (3-HB) levels. Opposite effects were observed in adenovirus-mediated ERK1/2 knockdown C57/B6J wild-type mice. Furthermore, autophagy and autophagy-related protein 7 (ATG7) expression were decreased or increased by ERK1/2 knockdown or activation, respectively, in primary hepatocytes and liver. Blockade of autophagy by the autophagy inhibitor chloroquine or adenovirus-mediated ATG7 knockdown reversed the ameliorated liver steatosis in recombinant adenoviruses construct expressing rat constitutively active MEK1 Ad-CA MEK1 db/db mice, decreased expression of genes related to fatty acid b-oxidation and TG export, and decreased serum 3-HB levels. Finally, ERK1/2 regulated ATG7 expression in a p38-dependent pathway. Taken together, these results identify a novel beneficial role for ERK1/2 in liver steatosis via promoting ATG7-dependent autophagy, which provides new insights into the mechanisms underlying liver steatosis and important hints for targeting ERK1/2 in treating liver steatosis.Nonalcoholic fatty liver disease involves a serious pathological change in liver (1). The initial stage of nonalcoholic fatty liver disease is liver steatosis, characterized by the excess deposition of triglyceride (TG) and/or cholesterol (TC) in liver (2). If uncontrolled, liver steatosis will progress to life-threatening diseases, such as liver cirrhosis and dysfunction (3). Abnormal hepatic lipid accumulation results from increased uptake of fatty acid/augmented de novo lipogenesis and/or decreased b-oxidation/impaired TG export (4).Autophagy, a cellular process that degrades intracellular organelles and proteins (5), has recently been demonstrated to regulate lipid metabolism (6,7). Lipid droplets are sequestered by autophagosome with the coordination of autophagy-related genes (ATGs). Autophagosome is then fused with lysosome (8) for the degradation of lipid droplets into free fatty acids (FFAs). FFAs are then degraded by mitochondrial b-oxidation to produce ATP or are reesterified into TG for storage (9). Impaired autophagy decreases hepatic fatty acid b-oxidation (FAO) and TG export and results in liver steatosis in mice (7,10), and fatty liver is ameliorated when hepatic autophagy is stimulated by certain compounds (11,12) or some signaling pathways (13) in various animal models.The mitogen-activated protein kinase-extracellular signalregulated kinase (MEK-ERK) signaling pathway is involved in a wide variety of cellular processes (14-16). Several lines of evidence, ...

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“…As one of the intracellular targets activated by such humoral factors, we found that glycogen synthase kinase (GSK)-3β-dependent Snail degradation occurs in hepatocytes to initiate their proliferation (Sekiya & Suzuki 2011). Snail is one of the zinc-finger transcription factors and involved in various cellular functions, including cell motility, differentiation, proliferation and survival (Nieto 2002).…”

Section: Liver Regeneration After Loss Of Liver Mass or Acute Hepaticmentioning

confidence: 99%

MBSJ MCC Young Scientist Award 2012 Liver regeneration: a unique and flexible reaction depending on the type of injury

Suzuki

2014

Genes to Cells

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The liver can be thought of as a mysterious organ, because it has an elegant regenerative capability. This phenomenon has been well known since ancient times and is already applied to medical treatments for severe hepatic disorders by transplanting portions of liver received from living donors. However, it was not until quite recently that the mechanism underlying the principle of liver regeneration was investigated more deeply. Recent advances in the technologies for characterizing cell properties and examining the molecular nature of cells are enabling us to understand what occurs in the regenerating liver. After acute liver damage, hepatocytes actively proliferate in response to external stimulation by humoral factors. However, in the chronically injured liver, hepatocytes cannot proliferate well, but biliary cells appearing after chronic liver damage form primitive ductules around portal veins of the liver. These biliary cells may have a multiple origin, including hepatocytes, and contain progenitor cells giving rise to both hepatocytes and biliary cells, or represent cells that can be directly converted into hepatocytes. Although liver regeneration is more complicated than we had thought, unremitting efforts by researchers will certainly connect the numerous findings obtained in basic research with the development of new therapeutic strategies for liver diseases.

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Glycogen synthase kinase 3β-dependent Snail degradation directs hepatocyte proliferation in normal liver regeneration

Cited by 36 publications

References 20 publications

GSK-3β suppresses the proliferation of rat hepatic oval cells through modulating Wnt/β-catenin signaling pathway

GSK-3β suppresses the proliferation of rat hepatic oval cells through modulating Wnt/β-catenin signaling pathway

Activation of ERK1/2 Ameliorates Liver Steatosis in Leptin Receptor–Deficient (db/db) Mice via Stimulating ATG7-Dependent Autophagy

MBSJ MCC Young Scientist Award 2012 Liver regeneration: a unique and flexible reaction depending on the type of injury

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