Compensatory recovery of liver mass by Akt-mediated hepatocellular hypertrophy in liver-specific STAT3-deficient mice

Haga, Sanae; Ogawa, Wataru; Inoue, Hiroshi; Terui, Keita; Ogino, Tetsuya; Igarashi, Rumi; Takeda, Kiyoshi; Akira, Shizuo; Enosawa, Shin; Furukawa, Hiroyuki; Todo, Satoru; Ozaki, Michitaka

doi:10.1016/j.jhep.2005.03.027

Cited by 94 publications

(110 citation statements)

References 48 publications

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“…The mechanisms regulating the size of the hepatocytes are largely unknown. Although the phosphatidylinositol-3 kinase/Akt pathway has been implicated in the regulation of cell size 33 and has been shown to be responsible for hepatocyte hypertrophy during liver regeneration, 34 Akt phosphorylation increased during transdifferentiation (Nishikawa et al, submitted for publication). As suggested by experiments using conditional HNF-4α knockout mice, in which small hepatocytes with decreased glycogen accumulation were found in the fetal liver (E18.5) with abnormally formed sinusoidal structures.…”

Section: Discussionmentioning

confidence: 99%

Recovery of Mature Hepatocytic Phenotype following Bile Ductular Transdifferentiation of Rat Hepatocytes in Vitro

Sone

Nishikawa

Nagahama

et al. 2012

The American Journal of Pathology

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We previously demonstrated that mature rat hepatocytes transdifferentiate to bile ductular cells when cultured in a three-dimensional collagen-rich matrix. Here, we show that the phenotype of transdifferentiated hepatocytes can be reversed by modulating culture conditions. Spheroidal aggregates of hepatocytes were cultured within a collagen gel matrix in the presence of serum and tumor necrosis factor-α. Spheroids transformed into ductular structures composed of small cuboidal cells, lost the expression of hepatocytic markers, while aberrantly expressed bile ductular markers. The transdifferentiated cells were then retrieved from the gels, plated on Matrigel-coated surfaces, and cultured in serum-free media. Cells spontaneously formed spheroidal aggregates and recovered hepatocytic phenotype. While Dexamethasone (Dex), which suppressed the phosphorylation of ERK and Jun N-terminal kinase, facilitated the recovery, the combination with interleukin-6 or oncostatin M resulted in the recovery of HNF-4α protein expression and the typical hepatocytic morphology and a decrease in the expression of bile ductular markers. A cDNA microarray analysis revealed that the hepatocyte-specific mRNA expression profile was recovered in these cells. Our results demonstrate that hepatocytes are able to recover their phenotypes following bile ductular transdifferentiation, suggesting that hepatocytic and bile ductular phenotypes may be mutually reversible.4

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Section: Discussionmentioning

confidence: 99%

Recovery of Mature Hepatocytic Phenotype following Bile Ductular Transdifferentiation of Rat Hepatocytes in Vitro

Sone

Nishikawa

Nagahama

et al. 2012

The American Journal of Pathology

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“…Previous studies reported that STAT3 plays an important role in constraining hepatocyte size after PHx. 14,30 Since IL-10 Ϫ/Ϫ mice had higher levels of hepatic STAT3 activation than wildtype mice, it is plausible to speculate that IL-10 Ϫ/Ϫ mice have a smaller size of hepatocytes than wild-type mice after PHx. Future studies are required to confirm this speculation.…”

Section: Il-10 Plays An Important Role In Tempering Inflammatory Respmentioning

confidence: 99%

Enhanced Liver Regeneration in IL-10–Deficient Mice after Partial Hepatectomy via Stimulating Inflammatory Response and Activating Hepatocyte STAT3

Yin

Wang

Park

et al. 2011

The American Journal of Pathology

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Emerging evidence suggests that proinflammatory cytokines, including tumor necrosis factor-␣ (TNF-␣) and interleukin-6 (IL-6), play a critical role in the initiation and progression of liver regeneration; however, relatively little is known about the role of antiinflammatory cytokine IL-10 in liver regeneration after partial hepatectomy (PHx). Here, we examined the role of IL-10 in liver regeneration using a model of PHx in several strains of genetically modified mice. After PHx, expression of IL-10 mRNA in the liver and spleen was significantly elevated. Such elevation was diminished in TLR4 mutant mice. Compared with wild-type mice, IL-10 ؊/؊ mice had higher levels of expression of proinflammatory cytokines (IL-6, TNF-␣, and IFN-␥) and inflammatory markers (CCR2 and F4/80) in the liver, as well as higher serum levels of proinflammatory cytokines after PHx. The number of neutrophils and macrophages was also higher in the livers of IL-10 ؊/؊ mice than in wild-type mice after PHx. Liver regeneration as determined by BrdU incorporation after PHx was higher in IL-10 ؊/؊ mice than in wild-type mice, which was associated with higher levels of activation of IL-6 downstream signal STAT3 in the liver. An additional deletion of STAT3 in hepatocytes significantly reduced liver regeneration in IL-10 ؊/؊ mice after PHx. Collectively, IL-10 plays an important role in negatively regulating liver regeneration via limiting inflammatory response and subsequently tempering hepatic STAT3 activation.

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“…[6][7][8][9][10][11] The importance of interleukin-6/signal transducer and activator of transcription-3 (STAT3) pathway in liver regeneration has been established, as reported by a number of researchers 12,13 using liver-specific Interleukin-6 or Stat3 knockout mice. Regarding STAT3, it was found that the defective mitotic response to hepatectomy in liver-specific Stat3-KO (LStat3KO) mice did not affect physical and functional liver regeneration at all.…”

mentioning

confidence: 99%

“…Regarding STAT3, it was found that the defective mitotic response to hepatectomy in liver-specific Stat3-KO (LStat3KO) mice did not affect physical and functional liver regeneration at all. 6 Although the hepatocyte mitotic response was suppressed or greatly delayed in L-Stat3KO mice, Akt and its associated signaling molecules such as p70 ribosomal S6 kinase (p70 S6K ), mammalian target of rapamycin (mTOR), and glycogen synthase kinase-3 were immediately phosphorylated after PH. These findings suggest that when cell proliferation is impaired, these molecules mediate a possible compensatory mechanism of liver regeneration.…”

mentioning

confidence: 99%

The survival pathways phosphatidylinositol-3 kinase (PI3-K)/phosphoinositide-dependent protein kinase 1 (PDK1)/Akt modulate liver regeneration through hepatocyte size rather than proliferation

et al. 2008

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Liver regeneration comprises a series of complicated processes. The current study was designed to investigate the roles of phosphoinositide-dependent protein kinase 1 (PDK1)-associated pathways in liver regeneration after partial hepatectomy (PH) using liver-specific Pdk1-knockout (L-Pdk1KO) and Pdk1/STAT3 double KO (L-DKO) mice. There was no liver regeneration, and 70% PH was lethal in L-Pdk1KO mice. Liver regeneration was severely impaired equally in L-Pdk1KO and L-DKO mice, even after nonlethal 30% PH. There was no cell growth (measured as increase of cell size) after hepatectomy in L-Pdk1KO mice, although the post-PH mitotic response was the same as in controls. As expected, hepatectomy did not induce hepatic Akt-phosphorylation (Thr308) in L-Pdk1KO mice, and post-PH phosphorylation of Akt, mammalian target of rapamycin (mTOR), p70 ribosomal S6 kinase (p70 S6K ), and S6 were also reduced. To examine the specific role of PDK1-associated signals, a "pif-pocket" mutant of PDK1, which allows PDK1 only to phosphorylate Akt, was used.

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Compensatory recovery of liver mass by Akt-mediated hepatocellular hypertrophy in liver-specific STAT3-deficient mice

Cited by 94 publications

References 48 publications

Recovery of Mature Hepatocytic Phenotype following Bile Ductular Transdifferentiation of Rat Hepatocytes in Vitro

Recovery of Mature Hepatocytic Phenotype following Bile Ductular Transdifferentiation of Rat Hepatocytes in Vitro

Enhanced Liver Regeneration in IL-10–Deficient Mice after Partial Hepatectomy via Stimulating Inflammatory Response and Activating Hepatocyte STAT3

The survival pathways phosphatidylinositol-3 kinase (PI3-K)/phosphoinositide-dependent protein kinase 1 (PDK1)/Akt modulate liver regeneration through hepatocyte size rather than proliferation

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