Stathmin 1 Induces Murine Hepatocyte Proliferation and Increased Liver Mass

Activation of PXR enhanced growth factor- and liver injury-mediated murine hepatocyte proliferation in vitro and in vivo. Mechanistic analyses suggest that activated PXR down-regulates the expression of cell-cycle suppressor genes by inhibiting their FOXO3-dependent transcription.

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Acceleration of murine hepatocyte proliferation by imazalil through the activation of nuclear receptor PXR

Drug Metabolism and Pharmacokinetics ◽

10.1016/j.dmpk.2018.09.180 ◽

2019 ◽

Vol 34 (1) ◽

pp. S51

Author(s):

Kouichi Yoshinari ◽

Shohei Yoshimaru ◽

Ryota Shizu ◽

Satoshi Tsuruta ◽

Yuto Amaike ◽

...

Keyword(s):

Nuclear Receptor ◽

Hepatocyte Proliferation ◽

Murine Hepatocyte

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Mesenchymal Stromal Cell-Derived Factors Promote Tissue Repair in a Small-for-Size Ischemic Liver Model but Do Not Protect against Early Effects of Ischemia and Reperfusion Injury

Journal of Immunology Research ◽

10.1155/2015/202975 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13 ◽

Cited By ~ 6

Author(s):

Suomi M. G. Fouraschen ◽

Joshua H. Wolf ◽

Luc J. W. van der Laan ◽

Petra E. de Ruiter ◽

Wayne W. Hancock ◽

...

Keyword(s):

Reperfusion Injury ◽

Mesenchymal Stromal Cell ◽

Stromal Cell ◽

Hepatocyte Proliferation ◽

Hepatic Tissue ◽

Ischemia And Reperfusion ◽

Liver Mass ◽

Ischemia And Reperfusion Injury ◽

Secreted Factors ◽

Small For Size

Loss of liver mass and ischemia/reperfusion injury (IRI) are major contributors to postresectional liver failure and small-for-size syndrome. Mesenchymal stromal cell- (MSC-) secreted factors are described to stimulate regeneration after partial hepatectomy. This study investigates if liver-derived MSC-secreted factors also promote liver regeneration after resection in the presence of IRI. C57BL/6 mice underwent IRI of 70% of their liver mass, alone or combined with 50% partial hepatectomy (PH). Mice were treated with MSC-conditioned medium (MSC-CM) or unconditioned medium (UM) and sacrificed after 6 or 24 hours (IRI group) or after 48 hours (IRI + PH group). Blood and liver tissue were analyzed for tissue injury, hepatocyte proliferation, and gene expression. In the IRI alone model, serum ALT and AST levels, hepatic tissue damage, and inflammatory cytokine gene expression showed no significant differences between both treatment groups. In the IRI + PH model, significant reduction in hepatic tissue damage as well as a significant increase in hepatocyte proliferation was observed after MSC-CM treatment.Conclusion. Mesenchymal stromal cell-derived factors promote tissue regeneration of small-for-size livers exposed to ischemic conditions but do not protect against early ischemia and reperfusion injury itself. MSC-derived factors therefore represent a promising treatment strategy for small-for-size syndrome and postresectional liver failure.

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Thyroid Hormone Treatment of Hypothyroid Rats Restores the Regenerative Capacity and the Mitochondrial Membrane Permeability Properties of the Liver after Partial Hepatectomy

Endocrinology ◽

10.1210/en.2004-0909 ◽

2004 ◽

Vol 145 (11) ◽

pp. 5121-5128 ◽

Cited By ~ 16

Author(s):

Loredana Moro ◽

Ersilia Marra ◽

Ferdinando Capuano ◽

Margherita Greco

Keyword(s):

Thyroid Hormone ◽

Membrane Permeability ◽

Partial Hepatectomy ◽

Mitochondrial Membrane ◽

Calcium Content ◽

Hepatocyte Proliferation ◽

Mitochondrial Calcium ◽

Liver Mass ◽

Mitochondrial Membrane Permeability ◽

Regenerative Capacity

Abstract We have investigated the effect of thyroid hormone on recovery of liver mass and on the mitochondrial membrane permeability properties during rat liver regeneration after 70% partial hepatectomy (PH). In the euthyroid state, liver weight starts to recover 24 h after PH and is completely restored 96 h after PH. Cyclosporin A (CsA)-sensitive mitochondrial permeability transition (MPT) occurs 24 h after PH, and it has been suggested to act in the signaling mechanism for hepatocyte proliferation. In this study we show that hypothyroidism delays recovery of the liver mass, being only 50% of the initial weight 96 h after PH, and alters the duration and mode of MPT occurrence, first inducing a CsA-insensitive swelling 24 h after PH, followed by a CsA-sensitive swelling 96 h after PH. The occurrence of both CsA-sensitive and -insensitive swelling is shown to be associated with an increase in mitochondrial calcium content. Concurrent with mitochondrial swelling, external release of matrix proteins from mitochondria, such as aspartate aminotransferase and malate dehydrogenase, is shown to be CsA insensitive 24 h after PH and CsA sensitive 96 h after PH. After thyroid hormone administration to hypothyroid rats, the liver regenerative capacity is restored, and the duration and mode of MPT occurrence as well as changes in mitochondrial calcium content become similar to those observed in the euthyroid condition. The results of the present study suggest the involvement of a mitochondria-mediated pathway in regulation of the liver regenerative process by thyroid hormone.

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Mechanisms of Liver Injury. I. TNF-α-induced liver injury: role of IKK, JNK, and ROS pathways

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00422.2005 ◽

2006 ◽

Vol 290 (4) ◽

pp. G583-G589 ◽

Cited By ~ 425

Author(s):

Robert F. Schwabe ◽

David A. Brenner

Keyword(s):

Liver Injury ◽

Liver Regeneration ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Hepatocyte Proliferation ◽

Liver Mass ◽

Hepatocyte Apoptosis ◽

Signaling Mechanisms ◽

Tnf Α

TNF-α activates several intracellular pathways to regulate inflammation, cell death, and proliferation. In the liver, TNF-α is not only a mediator of hepatotoxicity but also contributes to the restoration of functional liver mass by driving hepatocyte proliferation and liver regeneration. This review summarizes recent advances in TNF-α signaling mechanisms that demonstrate how the IKK, ROS, and JNK pathways interact with each other to regulate hepatocyte apoptosis and proliferation. Activation of these pathways is causatively linked to liver injury induced by concanavalin A, TNF-α, and ischemia-reperfusion and to liver regeneration and hepatocarcinogenesis. In light of recent findings, pharmacological inhibitors of JNK and IKK and antioxidants may be promising new tools for the treatment of hepatitis, ischemia-reperfusion injury, and hepatocellular carcinoma.

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Acceleration of murine hepatocyte proliferation by imazalil through the activation of nuclear receptor PXR

The Journal of Toxicological Sciences ◽

10.2131/jts.43.443 ◽

2018 ◽

Vol 43 (7) ◽

pp. 443-450 ◽

Cited By ~ 9

Author(s):

Shohei Yoshimaru ◽

Ryota Shizu ◽

Satoshi Tsuruta ◽

Yuto Amaike ◽

Makoto Kano ◽

...

Keyword(s):

Nuclear Receptor ◽

Hepatocyte Proliferation ◽

Murine Hepatocyte

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Constitutive Activation of the Nlrc4 Inflammasome Prevents Hepatic Fibrosis and Promotes Hepatic Regeneration after Partial Hepatectomy

Mediators of Inflammation ◽

10.1155/2015/909827 ◽

2015 ◽

Vol 2015 ◽

pp. 1-16 ◽

Cited By ~ 5

Author(s):

David A. DeSantis ◽

Chih-Wei Ko ◽

Lan Wang ◽

Peter Lee ◽

Colleen M. Croniger

Keyword(s):

Hepatic Fibrosis ◽

Partial Hepatectomy ◽

Molecular Mechanisms ◽

D1 Protein ◽

Hepatocyte Proliferation ◽

Brdu Incorporation ◽

Hepatic Regeneration ◽

Low Grade ◽

Liver Mass ◽

Constitutive Activation

TThe molecular mechanisms responsible for the development of hepatic fibrosis are not fully understood. The Nlrc4 inflammasome detects cytosolic presence of bacterial components, activating inflammatory cytokines to facilitate clearance of pathogens and infected cells. We hypothesized that low-grade constitutive activation of the Nlrc4 inflammasome may lead to induced hepatocyte proliferation and prevent the development of hepatic fibrosis. The gene of Nlrc4 contains two single nucleotide polymorphisms (SNPs), one located within the Nlrc4 promoter and one contained within exon 5. These SNPs regulate Nlrc4 gene transcription and activation as measured through gene reporter assays and IL-1βsecretion. The 17C-6 mice have increased IL-1βin plasma after chronic carbon tetrachloride (CCl4) administration compared to B6 mice. After two-thirds partial hepatectomy (2/3PH) 17C-6 mice have earlier restoration of liver mass with greater cyclin D1 protein and BrdU incorporation compared to B6 mice at several time points. These data reveal mild constitutive activation of the Nlrc4 inflammasome as the results of two SNPs, which leads to the stimulation of hepatocyte proliferation. The increased liver regeneration induces rapid liver mass recovery after hepatectomy and may prevent the development of hepatotoxin-induced liver fibrosis.

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Bid Regulates Murine Hepatocyte Proliferation by Controlling ER Calcium Homeostasis

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.749.5 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Min Li ◽

Hong‐min Ni ◽

Catherine J. Baty ◽

Wen‐xing Ding ◽

Xiaoyun Chen ◽

...

Keyword(s):

Calcium Homeostasis ◽

Hepatocyte Proliferation ◽

Murine Hepatocyte ◽

Er Calcium

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BMP4 is a novel paracrine inhibitor of liver regeneration

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00105.2012 ◽

2012 ◽

Vol 303 (11) ◽

pp. G1220-G1227 ◽

Cited By ~ 25

Author(s):

Nhue Do ◽

Rong Zhao ◽

Kevin Ray ◽

Karen Ho ◽

Martin Dib ◽

...

Keyword(s):

Liver Regeneration ◽

Bone Morphogenetic Proteins ◽

Transforming Growth Factor ◽

Critical Role ◽

Bmp Signaling ◽

Hepatocyte Proliferation ◽

High Dose ◽

Liver Mass ◽

Bmp4 Expression ◽

Specific Deletion

Transforming growth factor (TGF)-β family members exert strong effects on restoration of liver mass after injury. Bone morphogenetic proteins (BMPs) are members of the TGF-β family and are found in the liver, suggesting that these proteins may play a role in liver regeneration. We examined BMP signaling in the liver during hepatectomy. We found that BMP4 is constitutively expressed in the peribiliary stroma and endothelial cells of the liver and that expression is decreased after hepatectomy. Mice driven to maintain BMP4 expression in the liver display inhibited hepatocyte proliferation and restoration of liver mass after hepatectomy, suggesting that reduced BMP4 is necessary for normal regeneration. Consistent with this finding, hepatocyte-specific deletion of the BMP receptor activin receptor-like kinase 3 (Alk3) enhances regeneration and reduces phosphorylation of SMAD1/5/8, a transducer of BMP signaling. In contrast to experiments in wild-type mice, maintaining BMP4 levels has no effect on liver regeneration in hepatocyte-specific Alk3 null mice, providing evidence that BMP4 signals through Alk3 to inhibit liver regeneration. Consistent with these findings, the BMP4 antagonist Noggin enhances regeneration. Furthermore, high-dose BMP4 inhibits proliferation of primary hepatocytes and HepG2 cells in culture. These findings elucidate a new, potentially clinically relevant paradigm in which a constitutively expressed paracrine inhibitory factor plays a critical role in liver regeneration.

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