Identification of microRNAs during rat liver regeneration after partial hepatectomy and modulation by ursodeoxycholic acid

New gene regulation study tools such as microRNA (miRNA or miR) analysis may provide unique insights into the remarkable ability of the liver to regenerate. In addition, we have previously shown that ursodeoxycholic acid (UDCA) modulates mRNA levels during liver regeneration. Bile acids are also homeotrophic sensors of functional hepatic capacity. The present study was designed to determine whether miRNAs are modulated in rats following 70% partial hepatectomy (PH) and elucidate the role of UDCA in regulating miRNA expression during liver regeneration (LR). Total RNA was isolated from livers harvested at 3–72 h following 70% PH or sham operations, from both 0.4% (wt/wt) UDCA and control diet-fed animals. By using a custom microarray platform we found that several miRNAs are significantly altered after PH by >1.5-fold, including some previously described as modulators of cell proliferation, differentiation, and death. In particular, expression of miR-21 was increased after PH. Functional modulation of miR-21 in primary rat hepatocytes increased cell proliferation and viability. Importantly, UDCA was a strong inducer of miR-21 both during LR and in cultured HepG2 cells. In fact, UDCA feeding appeared to induce a sustained increase of proliferative miRNAs observed at early time points after PH. In conclusion, miRNAs, in particular miR-21, may play a significant role in modulating proliferation and cell cycle progression genes after PH. miR-21 is additionally induced by UDCA in both regenerating rat liver and in vitro, which may represent a new mechanism behind UDCA biological functions.

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930 IDENTIFICATION OF MICRORNAS DURING RAT LIVER REGENERATION AFTER PARTIAL HEPATECTOMY AND MODULATION BY URSODEOXYCHOLIC ACID

Journal of Hepatology ◽

10.1016/s0168-8278(10)60931-2 ◽

2010 ◽

Vol 52 ◽

pp. S360-S361

Author(s):

R.E. Castro ◽

X. Zhang ◽

D.M. Ferreira ◽

P.M. Borralho ◽

A.L. Sarver ◽

...

Keyword(s):

Liver Regeneration ◽

Ursodeoxycholic Acid ◽

Partial Hepatectomy ◽

Rat Liver ◽

Rat Liver Regeneration

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GDF11 impairs liver regeneration in mice after partial hepatectomy

Clinical Science ◽

10.1042/cs20190441 ◽

2019 ◽

Vol 133 (20) ◽

pp. 2069-2084

Author(s):

Wenjie Wang ◽

Xiao Yang ◽

Jiankun Yang ◽

Shenpei Liu ◽

Yongman Lv ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Liver Regeneration ◽

Signaling Pathway ◽

Partial Hepatectomy ◽

Neutralizing Antibodies ◽

Cell Cycle Progression ◽

Transforming Growth Factor

Abstract Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor (TGF)-β superfamily. The rejuvenative effect of GDF11 has been called into question recently, and its role in liver regeneration is unclear. Here, we investigated the pathophysiologic role of GDF11, as well as its plausible signaling mechanisms in a mouse model of partial hepatectomy (PH). We demonstrated that both serum and hepatic GDF11 protein expression increased following PH. Treatment with adeno-associated viruses-GDF11 and recombinant GDF11 protein severely impaired liver regeneration, whereas inhibition of GDF11 activity with neutralizing antibodies significantly improved liver regeneration after PH. In vitro, GDF11 treatment significantly delayed cell proliferation and induced cell-cycle arrest in α mouse liver 12 (AML12) cells. Moreover, GDF11 activated TGF-β-SMAD2/3 signaling pathway. Inhibition of GDF11-induced SMAD2/3 activity significantly blocked GDF11-mediated reduction in cell proliferation both in vivo and in vitro. In the clinical setting, GDF11 levels were significantly elevated in patients after hepatectomy. Collectively, these results indicate that rather than a ‘rejuvenating’ agent, GDF11 impairs liver regeneration after PH. Suppression of cell-cycle progression via TGF-β-SMAD2/3 signaling pathway may be a key mechanism by which GDF11 inhibits liver regeneration.

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Interleukin 18 accelerates the hepatic cell proliferation in rat liver regeneration after partial hepatectomy

Gene ◽

10.1016/j.gene.2013.12.062 ◽

2014 ◽

Vol 537 (2) ◽

pp. 230-237 ◽

Cited By ~ 11

Author(s):

Jihong Zhang ◽

Chengkai Ma ◽

Yunqing Liu ◽

Gang Yang ◽

Yun Jiang ◽

...

Keyword(s):

Cell Proliferation ◽

Liver Regeneration ◽

Partial Hepatectomy ◽

Rat Liver ◽

Hepatic Cell ◽

Interleukin 18 ◽

Rat Liver Regeneration

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Estrogen Accelerates Cell Proliferation through Estrogen Receptor α during Rat Liver Regeneration after Partial Hepatectomy

ACTA HISTOCHEMICA ET CYTOCHEMICA ◽

10.1267/ahc.17003 ◽

2017 ◽

Vol 50 (1) ◽

pp. 39-48 ◽

Cited By ~ 9

Author(s):

Baatarsuren Batmunkh ◽

Narantsog Choijookhuu ◽

Naparee Srisowanna ◽

Uugantsetseg Byambatsogt ◽

Phyu Synn Oo ◽

...

Keyword(s):

Cell Proliferation ◽

Estrogen Receptor ◽

Liver Regeneration ◽

Partial Hepatectomy ◽

Rat Liver ◽

Estrogen Receptor Α ◽

Rat Liver Regeneration

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Expression profiles uncover the relationship between erythropoietin and cell proliferation in rat hepatocytes after a partial hepatectomy

Cellular & Molecular Biology Letters ◽

10.2478/s11658-014-0198-0 ◽

2014 ◽

Vol 19 (3) ◽

Cited By ~ 4

Author(s):

Jihong Zhang ◽

Yajuan Yang ◽

Tingting He ◽

Yunqing Liu ◽

Yun Zhou ◽

...

Keyword(s):

Cell Proliferation ◽

Liver Regeneration ◽

Signaling Pathway ◽

Partial Hepatectomy ◽

Rat Liver ◽

Target Genes ◽

Expression Profiles ◽

Synergetic Effect ◽

Rat Liver Regeneration ◽

Percoll Density Gradient Centrifugation

AbstractErythropoietin (EPO) has a beneficial effect on hepatic cell proliferation during liver regeneration. However, the underlying mechanism has not yet been elucidated. To uncover the proliferation response of EPO in rat liver regeneration after partial hepatectomy (PH) at the cellular level, hepatocytes (HCs) were isolated using Percoll density gradient centrifugation. The genes of the EPO-mediated signaling pathway and the target genes of the transcription factor (TF) in the pathway were identified in a pathway and TF database search. Their expression profiles were then detected using Rat Genome 230 2.0 Microarray. The results indicated that the EPO-mediated signaling pathway is involved in 19 paths and that 124 genes participate, of which 32 showed significant changes and could be identified as liver regeneration-related genes. In addition, 443 targets regulated by the TFs of the pathway and 60 genes associated with cell proliferation were contained in the array. Subsequently, the synergetic effect of these genes in liver regeneration was analyzed using the E(t) mathematical model based on their expression profiles. The results demonstrated that the E(t) values of paths 3, 8, 12 and 14–17 were significantly strengthened in the progressing phase of liver regeneration through the RAS/MEK/ERK or PI3K/AκT pathways. The synergetic effect of the target genes, in parallel with target-related cell proliferation, was also enhanced 12–72 h after PH, suggesting a potential positive effect of EPO on HC proliferation during rat liver regeneration. These data imply that the EPO receptor may allow EPO to promote HC proliferation through paths 3, 8, 12 and 14–17, mediating the RAS/MEK/ERK and PI3K/AκT pathways in rat liver regeneration after PH.

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Identification of genes early responsive to gamma-irradiation in isolated rat hepatocytes in vitro and rat liver in vivo by cDNA array gene expression analysis

Zeitschrift für Gastroenterologie ◽

10.1055/s-2005-920060 ◽

2005 ◽

Vol 43 (05) ◽

Author(s):

DS Batusic ◽

H Christiansen ◽

B Saile ◽

RM Hermann ◽

J Dudas ◽

...

Keyword(s):

Gene Expression ◽

Gamma Irradiation ◽

Rat Liver ◽

Gene Expression Analysis ◽

Cdna Array ◽

Rat Hepatocytes ◽

Isolated Rat Hepatocytes ◽

Isolated Rat

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Turnover of total proteins and ornithine aminotransferase during liver regeneration in rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1980.238.1.e46 ◽

1980 ◽

Vol 238 (1) ◽

pp. E46-E52

Author(s):

S. L. Augustine ◽

R. W. Swick

Keyword(s):

Amino Acids ◽

Liver Regeneration ◽

Protein Degradation ◽

Partial Hepatectomy ◽

Free Amino ◽

Liver Protein ◽

Ornithine Aminotransferase ◽

Fractional Rate

The recovery of approximately 40% of the total liver protein during the first day after partial hepatectomy was shown to be due to the near cessation of protein breakdown rather than to an increase in protein synthesis. The decrease in degradation of total protein was less if rats were adrenalectomized or protein-depleted prior to partial hepatectomy. The effect of these treatments originally suggested that changes in free amino acid levels in liver might be related to the rate of protein degradation. However, no correlation was found between levels of total free amino acids and rates of breakdown. Measurements of individual amino acids during liver regeneration suggested that levels of free methionine and phenylalanine, amino acids that have been found to lower rates of protein degradation in vitro, are not correlated with rates of breakdown in vivo. The difference between the fractional rate of ornithine aminotransferase degradation (0.68/day and 0.28/day in sham-hepatectomized and partially hepatectomized rats, respectively) was sufficient to account for the higher level of this protein 3 days after surgery in the latter group.

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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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