Overturning the paradigm that IL6 signaling drives liver regrowth while shining light on a new therapeutic target for regenerative medicine

It is accepted that IL6 signaling in hepatocytes, mediated via glycoprotein 130 (gp130), is beneficial and that HyperIL6 promotes liver regeneration by activating STAT3. Recently, autocrine IL11 activity, which also signals via gp130 and ERK, was found to be hepatotoxic. Here we examined whether the beneficial effects of HyperIL6 could reflect unappreciated competitive inhibition of IL11 signaling. In hepatocytes, HyperIL6 inhibited N-acetyl-p-aminophenol (APAP)-induced cell death that mimicked inhibition of IL11 signaling and was unrelated to STAT3 phosphorylation. In mice, expression of HyperIL6 reduced liver damage due to IL11 dosing or APAP and promoted hepatic regeneration in a STAT3-independent manner. Following APAP, mice deleted for Il11 were protected from liver failure and exhibited spontaneous regeneration. Despite robustly activating STAT3, HyperIL6 had no beneficial effect in Il11 null mice. These data overturn the premise that IL6 promotes liver regeneration, show STAT3 activation to be redundant and suggest IL11 as a focus for regenerative medicine.

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The pro-regenerative effects of hyperIL6 in drug-induced liver injury are unexpectedly due to competitive inhibition of IL11 signaling

eLife ◽

10.7554/elife.68843 ◽

2021 ◽

Vol 10 ◽

Author(s):

Jinrui Dong ◽

Sivakumar Viswanathan ◽

Eleonora Adami ◽

Sebastian Schafer ◽

Fathima F Kuthubudeen ◽

...

Keyword(s):

Liver Regeneration ◽

Competitive Inhibition ◽

Hepatic Regeneration ◽

Drug Induced ◽

Erk Activation ◽

Drug Induced Liver Injury ◽

Beneficial Effects ◽

Stat3 Signaling ◽

Mouse Hepatocytes ◽

Target Effects

It is generally accepted that IL6-mediated STAT3 signaling in hepatocytes, mediated via glycoprotein 130 (gp130; IL6ST), is beneficial and that the synthetic IL6:IL6ST fusion protein (HyperIL6) promotes liver regeneration. Recently, autocrine IL11 activity that also acts via IL6ST but uses ERK rather than STAT3 to signal, was found to be hepatotoxic. Here we examined whether the beneficial effects of HyperIL6 could reflect unappreciated competitive inhibition of IL11-dependent IL6ST signaling. In human and mouse hepatocytes, HyperIL6 reduced N-acetyl-p-aminophenol (APAP)-induced cell death independent of STAT3 activation and instead, dose-dependently, inhibited IL11-related signaling and toxicities. In mice, expression of HyperIl6 reduced ERK activation and promoted STAT3-independent hepatic regeneration (PCNA, Cyclin D1, Ki67) following administration of either IL11 or APAP. Inhibition of putative intrinsic IL6 trans-signaling had no effect on liver regeneration in mice. Following APAP, mice deleted for Il11 exhibited spontaneous liver repair but HyperIl6, despite robustly activating STAT3, had no effect on liver regeneration in this strain. These data show that synthetic IL6ST binding proteins such as HyperIL6 can have unexpected, on-target effects and suggest IL11, not IL6, as important for liver regeneration.

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Cerium oxide nanoparticles improve liver regeneration after acetaminophen-induced liver injury and partial hepatectomy in rats

Journal of Nanobiotechnology ◽

10.1186/s12951-019-0544-5 ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 7

Author(s):

Bernat Córdoba-Jover ◽

Altamira Arce-Cerezo ◽

Jordi Ribera ◽

Montse Pauta ◽

Denise Oró ◽

...

Keyword(s):

Liver Injury ◽

Liver Regeneration ◽

Cerium Oxide ◽

Partial Hepatectomy ◽

Experimental Models ◽

Cerium Oxide Nanoparticles ◽

Hepatic Regeneration ◽

Oxide Nanoparticles ◽

Acetyl Cysteine

Abstract Background and aims Cerium oxide nanoparticles are effective scavengers of reactive oxygen species and have been proposed as a treatment for oxidative stress-related diseases. Consequently, we aimed to investigate the effect of these nanoparticles on hepatic regeneration after liver injury by partial hepatectomy and acetaminophen overdose. Methods All the in vitro experiments were performed in HepG2 cells. For the acetaminophen and partial hepatectomy experimental models, male Wistar rats were divided into three groups: (1) nanoparticles group, which received 0.1 mg/kg cerium nanoparticles i.v. twice a week for 2 weeks before 1 g/kg acetaminophen treatment, (2) N-acetyl-cysteine group, which received 300 mg/kg of N-acetyl-cysteine i.p. 1 h after APAP treatment and (3) partial hepatectomy group, which received the same nanoparticles treatment before partial hepatectomy. Each group was matched with vehicle-controlled rats. Results In the partial hepatectomy model, rats treated with cerium oxide nanoparticles showed a significant increase in liver regeneration, compared with control rats. In the acetaminophen experimental model, nanoparticles and N-acetyl-cysteine treatments decreased early liver damage in hepatic tissue. However, only the effect of cerium oxide nanoparticles was associated with a significant increment in hepatocellular proliferation. This treatment also reduced stress markers and increased cell cycle progression in hepatocytes and the activation of the transcription factor NF-κB in vitro and in vivo. Conclusions Our results demonstrate that the nanomaterial cerium oxide, besides their known antioxidant capacities, can enhance hepatocellular proliferation in experimental models of liver regeneration and drug-induced hepatotoxicity.

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Beneficial Effect of Hyperbaric Oxygen Therapy on Liver Regeneration after 90% Hepatectomy in Rats

European Surgical Research ◽

10.1159/000081643 ◽

2004 ◽

Vol 36 (6) ◽

pp. 350-356 ◽

Cited By ~ 14

Author(s):

K. Nagamine ◽

T. Kubota ◽

S. Togo ◽

Y. Nagashima ◽

M. Mori ◽

...

Keyword(s):

Beneficial Effect ◽

Liver Regeneration ◽

Hyperbaric Oxygen ◽

Hyperbaric Oxygen Therapy ◽

Oxygen Therapy

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Implication for Bone Marrow Derived Stem Cells in Hepatocyte Regeneration after Orthotopic Liver Transplantation

International Journal of Hepatology ◽

10.1155/2013/310612 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

N. Pilat ◽

L. Unger ◽

G. A. Berlakovich

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Liver Transplantation ◽

Liver Regeneration ◽

Orthotopic Liver Transplantation ◽

Liver Tissue ◽

Hepatic Regeneration ◽

Liver Growth ◽

Cell Source ◽

The Impact

The liver has the outstanding ability to regenerate itself and restore parenchymal tissue after injury. The most common cell source in liver growth/regeneration is replication of preexisting hepatocytes although liver progenitor cells have been postulated to participate in liver regeneration in cases of massive injury. Bone marrow derived hematopoietic stem cells (BM-HSC) have the formal capacity to act as a source for hepatic regeneration under special circumstances; however, the impact of this process in liver tissue maintenance and regeneration remains controversial. Whether BM-HSC are involved in liver regeneration or not would be of particular interest as the cells have been suggested to be an alternative donor source for the treatment of liver failure. Data from murine models of liver disease show that BM-HSC can repopulate liver tissue and restore liver function; however, data obtained from human liver transplantation show only little evidence for liver regeneration by this mechanism. The cell source for liver regeneration seems to depend on the nature of regeneration process and the extent of injury; however, the precise mechanisms still need to be resolved. Current data suggest, that in human orthotopic liver transplantation, liver regeneration by BM-HSC is a rather rare event and therefore not of clinical relevance.

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Hydrocortisone decreases apoptosis in jejunum of horses subjected to experimental ischemia and reperfusion

Pesquisa Veterinária Brasileira ◽

10.1590/s0100-736x2011000600002 ◽

2011 ◽

Vol 31 (6) ◽

pp. 471-476 ◽

Cited By ~ 2

Author(s):

Geraldo Eleno S. Alves ◽

Heloisa M.F. Mendes ◽

Tiago G.S. Alves ◽

Rafael R. Faleiros ◽

Anilton C. Vasconcelos ◽

...

Keyword(s):

Cell Death ◽

Time Course ◽

Apoptotic Cell ◽

Treated Group ◽

Apoptotic Cell Death ◽

Apoptotic Cells ◽

Ischemia And Reperfusion ◽

Beneficial Effects ◽

Time Zero ◽

Venous Ischemia

In order to evaluate the effect of hydrocortisone on apoptosis in the jejunum of horses subjected to ischemia and reperfusion, ten horses were paired and grouped into two groups - treated (n=5) and non treated (n=5). Segments of the jejunum were used as controls (C), or as venous ischemia (VIsc), which were subjected to 2h of ischemia followed by 2 or 12h of reperfusion. C samples were collected at time zero (prior to ischemia) and VIsc samples were collected at 2h of ischemia and at 2 and 12h of reperfusion. TUNEL positive apoptotic cells were counted in 10 microscopical fields in deep mucosa from each horse throughout the time course. After 12h of reperfusion, the number of apoptotic cells in treated group were significantly lower than in untreated animals, indicating that hydrocortisone inhibits apoptosis. These results indicate that hydrocortisone has a beneficial effects favoring the maintenance of jejunal integrity in horses with ischemia and reperfusion injuries by preventing apoptotic cell death.

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The Role of Insulin in Hepatic Regeneration: A New Frontier in Liver Function. An Invited Brief Commentary on “Insulin Metabolism and Assessment of Hepatic Insulin Extraction During Liver Regeneration. A Study in a Rat Model”

Journal of Investigative Surgery ◽

10.1080/08941939.2018.1488020 ◽

2018 ◽

Vol 33 (1) ◽

pp. 77-78

Author(s):

Gaetano Gallo

Keyword(s):

Liver Function ◽

Liver Regeneration ◽

Rat Model ◽

Hepatic Regeneration ◽

Insulin Metabolism ◽

New Frontier ◽

Hepatic Insulin Extraction

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Effectiveness of aronia berries for reduction of mild fibrosis and gene expression analysis in livers from mice fed a high-fat diet with aronia berries

Functional Foods in Health and Disease ◽

10.31989/ffhd.v6i3.245 ◽

2016 ◽

Vol 6 (3) ◽

pp. 144 ◽

Cited By ~ 5

Author(s):

Takuya Yamane ◽

Miyuki Kozuka ◽

Yoshio Yamamoto ◽

Yoshihisa Nakano ◽

Takenori Nakagaki ◽

...

Keyword(s):

Gene Expression ◽

Liver Fibrosis ◽

Beneficial Effect ◽

Rna Sequencing ◽

Expression Analysis ◽

High Fat Diet ◽

Gene Expression Analysis ◽

High Fat ◽

Expression Levels ◽

Beneficial Effects

Background: Aronia berries have many potential effects on health, including an antioxidant effect, effect for antimutagenesis, hepatoprotection and cardioprotection, an antidiabetic effect and inhibition of cancer cell proliferation. Previous human studies have shown that aronia juice may be useful for treatment of obesity disorders.Objective: To reveal relationship between beneficial effect and the gene expression change by aronia berries, we analyzed mice livers using RNA sequencing and RT-qPCR.Method: At 28 days after starting a normal diet, a high fat diet and a high-fat diet containing 10% freeze-dried aronia berries, serum was obtained from veins of mice after isoflurane anesthesia, and liver tissues were isolated and weighed. Triglyceride, total cholesterol and LDL cholesterol levels were measured and total RNAs were extracted. cDNA libraries were prepared according to Illumina protocols and sequenced using an Illumina HiSeq2500 to perform 100 paired-end sequencing. RNA-sequence reads mapping was performed using a DNA nexus. Gene expression analysis was performed. The liver tissue specimens were fixed and embedded in paraffin. After 5-mm-thick paraffin sections had been cut, they were stained with hematoxylin-eosin using the standard procedure and also with Sirius Red.Results: In this study, we found that mild fibrosis induced by a high-fat diet was reduced in livers of mice fed a high-fat diet containing aronia berries. RNA sequencing and RT-qPCR analyses revealed that gene expression levels of Igfbp1 and Gadd45g were increased in livers from mice fed a high-fat diet containing aronia berries. Furthermore, results of an enzyme-linked immunoassay showed that a secreted protein levels of FABP1 and FABP4 were reduced in serum from mice fed a high-fat diet containing aronia berries. The results suggest that aronia berries have beneficial effects on mild fibrosis in liver.Conclusion: Aronia berries have a beneficial effect on liver fibrosis. The recovery from liver fibrosis is associated with expression levels of Gadd45g and Igfbp1 in the liver. The beneficial effects of aronia berries on liver fibrosis reduce the risk of liver cancer diseases and insulin resistance, resulting in reduction of serum FABP1 and FABP4 levels.Keywords: aronia; fibrosis; liver; Igfbp1; Gadd45g

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Beneficial effects of alternative lighting schedules on the incidence of ascites and on metabolic parameters of broiler chickens

Acta Veterinaria Hungarica ◽

10.1556/avet.51.2003.4.9 ◽

2003 ◽

Vol 51 (4) ◽

pp. 513-520 ◽

Cited By ~ 13

Author(s):

M. Hassanzadeh ◽

M. H. Bozorgmehri Fard ◽

J. Buyse ◽

E. Decuypere

Keyword(s):

Beneficial Effect ◽

Sea Level ◽

Minimum Temperature ◽

Broiler Chickens ◽

Right Ventricular Failure ◽

Ventricular Failure ◽

Temporary Reduction ◽

Relative Growth ◽

Beneficial Effects ◽

The Third

The beneficial effects of different lighting programmes on the incidence of ascites was investigated in an experiment with 360 three-day-old male broiler chickens. At 3 days of age, chicks were randomly divided over three rooms in a high-altitude farm, 2000 m above sea level. During days 14 to 28 ambient temperature decreased during the night but the minimum temperature did not descend below 15°C. In the first room the continuous lighting schedule (CL, 23L:1D) was maintained and in the second room an intermittent lighting schedule (IL, 1L:3D), repeated six times daily, was imposed from 3 days of age. In the third room, an increasing photoperiod schedule (IP, 4 to 14 days, 6L:18D; 15 to 21 days, 10L:14D; 22 to 28 days, 14L:10D; 29 to 35 days, 18L:6D; 36 to 42 days, 23L:1D) was provided. Mortality associated with right ventricular failure and ascites was numerically lower in birds reared under the IL and IP schedules compared to birds reared under the CL schedule, which can be attributed to the temporary reduction in relative growth and feed intake in IL and IP birds. It was concluded that the beneficial effect of lighting schedules could be due to a reduced metabolic rate as a consequence of the altered growth trajectory, as also reflected in the lower haematocrit and plasma T3 levels of IL and IP birds compared to CL birds.

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