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PubMed2002

[Effect of recombinant human augmenter of liver regeneration on gene expression of tissue inhibitor of metalloproteinase-1 in rat with experimental liver fibrosis].

OBJECTIVE: To investigate the influence of recombinant human augmenter of liver regeneration (hALR) on gene expression of tissue inhibitor of metalloproteinase-1 (TIMP1) in rat with experimental liver fibrosis. METHODS: Carbon tetrachloride was injected into the peritoneal cavities of 150 rats twice a week for 8 weeks. Albumin sensitization and caudal vein attack were conducted to another 136 rats for the duration of 3.5 months, so as to establish two kinds of animal model of experimental liver fibrosis. Recombinant hALR at different doses was given during the process of model making. Specimens of liver were taken at different time-points, then the total RNA of liver tissues was isolated and TIMP1 gene expression levels were measured by reverse transcription polymerase chain reaction. RESULTS: In both rat models, TIMP(1) gene expression levels increased gradually during the process of model making. The TIMP(1) gene expression level in CCl4 model treated with low dose hALR was 0.86 +/- 0.13, 1.77 +/- 0.23, 2.78 +/- 0.36, and 3.76 +/- 0.50 respectively 2, 4, 6, and 8 weeks after the beginning of model making, all lower than those in the model group, however, without significant difference. The TIMP(1) gene expression level in CCl4 model treated with high dose hALR was 0.63 +/- 0.10, 1.18 +/- 0.20, 1.89 +/- 0.30, 2.63 +/- 0.33 respectively 2, 4, 6, and 8 weeks after the beginning of model making, significantly lower than those in CCl4 model treated with low dose hALR. In the albumin model group the TIMP(1) gene expression level showed no change during albumin sensitization, significantly increased during caudal vein attack, and reached the peak after medel making. The TIMP(1) gene expression level was lower in albumin model treated with low dose hALR during and after caudal vein attack than in the model group and negative control group, however, without significant difference (both P > 0.05). The TIMP(1) gene expression level in albumin model treated with high dose hALR was 2.33 +/- 0.36 and 4.02 +/- 0.53 during and after caudal vein attack respectively, significantly lower than those in CCl4 model group (0.99 +/- 0.14, 2.03 +/- 0.30, 2.99 +/- 0.43, and 4.13 +/- 0.44 respectively 2, 4, 6, and 8 weeks after beginning of model making respectively) and those in albumin model without hALR treatment and that with low dose hALR (4.13 +/- 0.60 and 5.99 +/- 0.83, and 3.70 +/- 0.82 and 5.63 +/- 0.89 during and after caudal vein attack respectively), and negative control group. CONCLUSION: High dose recombinant human augmenter of liver regeneration is effective in inhibiting gene expression of TIMP(1) in experimental liver fibrosis.

Animals↗
PubMed2003

Involvement of nuclear phosphatidylinositol-dependent phospholipases C in cell cycle progression during rat liver regeneration.

Nuclear lipid metabolism is involved in the regulation of cell proliferation. Modulation of the expression and activity of nuclear PI-phospholipase C (PI-PLC) has been reported during liver regeneration after partial hepatectomy, although it has not been determined whether different PLC isoforms play specific roles in the regulation of cell cycle progression. Here, we report evidence that the increased activity of nuclear PLCs in regenerating rat liver occurs before the peak of DNA replication and involves the enzyme activity associated to the chromatin and not that associated to the nuclear membrane. Immunocytochemical analyses indicate that PI-PLC beta(1) isoform is exclusively localized at the chromatin level, PI-PLC beta(1) co-localizes with DNA replication sites much more than PI-PLC gamma(1), which is also present at the nuclear envelope. These findings and the increased amount of PI-PLC gamma(1) occurring after the peak of DNA replication suggest that PI-PLC beta(1) and gamma(1) play different roles in cell cycle progression during regenerating liver. The increased activity of PI-PLC beta(1) constitutively present within the hepatocyte nucleus, should trigger DNA replication, whereas PI-PLC gamma(1) should be involved in G2/M phase transition through lamin phosphorylation.

Animals↗
PubMed1993

Effect of ageing on rat liver regeneration after partial hepatectomy.

The effect of ageing on liver regeneration after two-thirds partial hepatectomy was evaluated using rats of 6 and 60 weeks of age. The induction of thymidylate synthase and thymidine kinase, which are rate-determining enzymes of DNA synthesis in liver regeneration, delayed by 24 h and the maximal activities were significantly lower in old rats. Effects of aging on liver weight and synthesis of DNA, RNA and protein were discussed quantitatively in terms of the relative restoration yield deduced from the comparison with the young animals.

Aging↗
PubMed1990

Liver regeneration is associated with increased expression of the insulin-like growth factor-II/mannose-6-phosphate receptor.

The process of liver regeneration involves the concerted action of certain growth factors, which stimulate hepatocyte proliferation, and other antiproliferative factors, which prevent uncontrolled growth of this organ. Some of the biological actions of insulin-like growth factor-II (IGF-II), a mitogenic polypeptide closely related to insulin, may be mediated by the IGF-II receptor. This receptor consists of a single chain extracellular domain and a very small cytoplasmic domain, and can bind lysosomal enzymes that contain mannose-6-phosphate (M-6-P) residues. Since these enzymes may be involved in remodelling processes in certain tissues, we measured the expression of the IGF-II/M-6-P receptor in the liver after subtotal hepatectomy. Binding of [125I]IGF-II to crude plasma membranes from regenerating liver was maximal 2 days after hepatectomy (4.9% specific binding/60 micrograms protein) and subsequently decreased. Both control livers (livers removed at the time of operation) and sham-operated control livers demonstrated specific [125I]IGF-II binding of 1.1% throughout the experimental period. This increase in binding in regenerating liver was shown to be associated with an increase in the concentration of IGF-II receptor protein by means of Western blot analysis using a polyclonal anti-IGF-II/M-6-P receptor antiserum (3637). Similarly, steady state levels of IGF-II/M-6-P receptor mRNA, measured by solution hybridization/RNase protection assays, were significantly increased in the regenerating liver (2.0-fold over the control value 2 days after hepatectomy). Five and 10 days postsurgery, the levels of IGF-II receptor mRNA were markedly reduced, and they were even lower than the levels in control livers.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

[Synthesis of mitochondrial proteins coded in the nucleus and mitochondria of the intact and regenerating liver of rats of various ages].

Rate of protein synthesis of rat liver tissue was decreased with ageing in mitochondria but not in nuclear fraction. Stimulation of the mitochondrial ionogenesis by means of partial hepatectomy made the effects of age more distinct. The rate of protein synthesis in mitochondria was distinctly higher in adult rats as compared with the old animals. Electrophoretic separation of labelled products of mitochondrial translation enabled to find more than 20 individual polypeptides and showed that the age-dependent decrease in the synthesis rate was dissimilar for various proteins.

Aging↗
PubMed1994

Proliferating cell nuclear antigen, plasma fibronectin, and liver regeneration rate after seventy percent hepatectomy in normal and cirrhotic rats.

BACKGROUND: The difference in liver regeneration rate in relation to proliferating cell nuclear antigen (PCNA) and plasma fibronectin level in the cirrhotic and control liver after 70% hepatectomy were examined in the rat. METHODS: Liver cirrhosis was induced by intraperitoneal injection of thioacetamide for 12 weeks; rats without thioacetamide administration served as controls. On the day before and days 1, 2, 3, and 7 after 70% hepatectomy, PCNA labeling index of hepatocyte, plasma fibronectin level, and percentage of the initial liver weight were determined. RESULTS: Liver regeneration rate as expressed by percent of initial liver weight was impaired in the cirrhotic liver, and significantly lower regeneration rate was observed on days 3 and 7 after hepatectomy in the cirrhotic rats as compared with controls. PCNA labeling index was higher in the cirrhotic liver before hepatectomy. Little change of PNA labeling index was observed in the cirrhotic liver, although the index increased significantly in the control liver; significantly higher values were observed on days 1, 2, and 3, with the maximal value on day 2 after hepatectomy. The plasma fibronectin level was significantly lower in the cirrhotic rat before and after hepatectomy. CONCLUSIONS: The results show that liver regeneration is impaired in the cirrhotic liver associated with little activation of PCNA and with lower plasma fibronectin level.

Animals↗
PubMed2004

The role of midkine and pleiotrophin in liver regeneration.

BACKGROUND/PURPOSE: We studied roles of two closely related heparin-binding growth factors, midkine (MK) and plieotrophin (PTN) in the processes of liver regeneration after partial hepatectomy. METHODS: Liver regeneration was comparatively analyzed using mice deficient in the MK gene (Mdk), mice deficient in the pleiotrophin gene (Ptn) and wild-type mice. RESULTS: Migration of neutrophils and macrophages to the liver 1-5 days after partial hepatectomy was suppressed in Mdk (-/-) mice. Liver damage as assessed by serum aspartate aminotransferase was also less severe in the deficient mice. On the other hand, cell growth in the liver was generally suppressed in the deficient mice 3-14 days after partial hepatectomy. The weight of the liver 7 and 14 days after partial hepatectomy was significantly less in Mdk (-/-) mice than wild-type mice. Very similar results were obtained using Ptn (-/-) mice except that a significant difference in the repaired liver weight was not observed between Ptn (-/-) mice and wild-type mice. CONCLUSIONS: MK and PTN are involved both in the inflammatory and reparative processes after partial hepatectomy, and as a whole are beneficial for liver regeneration.

Animals↗
PubMed2006

Expression pattern and action analysis of genes associated with the responses to chemical stimuli during rat liver regeneration.

AIM: To study the genes associated with the responses to chemokines, nutrients, inorganic substances, organic substances and xenobiotics after rat partial hepatectomy (PH) at transcriptional level. METHODS: The associated genes involved in the five kinds of responses were obtained from database and literature, and the gene expression changes during liver regeneration in rats were checked by the Rat Genome 230 2.0 array. RESULTS: It was found that 60, 10, 9, 6, 26 genes respectively participating in the above five kinds of responses were associated with liver regeneration. The numbers of initially and totally expressed genes occurring in the initial phase of liver regeneration (0.5-4 h after PH), G(0)/G(1) transition (4-6 h after PH), cell proliferation (6-66 h after PH), cell differentiation and structure-functional reconstruction (66-168 h after PH) were 51, 19, 52, 6 and 51, 43, 98, 68 respectively, illustrating that the associated genes were mainly triggered in the initiation and transition stages, and functioned at different phases. According to their expression similarity, these genes were classified into 5 groups: only up-regulated (47), predominantly up-regulated (18), only down-regulated (24), predominantly down-regulated (10), and up- and down-regulated (8). The total times of their up-regulated and down-regulated expression were 441 and 221, demonstrating that the number of up-regulated genes is more than that of the down-regulated genes. Their time relevance and gene expression patterns were classified into 14 and 26 groups, showing that the cell physiological and biochemical activities were staggered, diversified and complicated during liver regeneration in rats. CONCLUSION: The chemotaxis was enhanced mainly in the forepart and metaphase of LR. The response of regenerating liver to nutrients and chemical substances was increased, whereas that to xenobiotics was not strong. One hundred and seven genes associated with LR play important roles in the responses to chemical substances.

Animals↗
PubMed2004

Liver regeneration in FGF-2-deficient mice: VEGF acts as potential functional substitute for FGF-2.

BACKGROUND/AIMS: The angiogenic properties, its role in mesoderm differentiation and cell culture studies implicate an important role of fibroblast growth factor (FGF-2) in liver regeneration. The aim of the study was to evaluate this role in a FGF-2 knockout mouse model. METHODS: Liver regeneration after left hemihepatectomy (partial hepatectomy, PH) was evaluated in homozygous FGF-2 deficient (-/-) mice (male C57BL/6J) and their FGF-2 competent (+/+) littermates (controls) (day 0-10). RESULTS: FGF-2-(-/-) mice displayed normal dynamics in liver regeneration. FGF-2 protein was overexpressed 4 days post PH in controls. BrdU incorporation showed a biphasic pattern in FGF-2-(-/-) mice, whereas it decreased continuously after one peak (day 2) in controls. In FGF-2-(-/-) livers hepatic growth factor mRNA post PH was 1 day longer decreased and markedly less elevated thereafter compared with control. Vascular endothelial growth factor (VEGF) mRNA levels were clearly increased in FGF-2-(-/-) mice pre- and postoperatively in contrast to controls. VEGF protein levels in livers of FGF-2-(-/-) mice were elevated preoperatively, but similar in both groups after PH. With SU5416, a VEGF-receptor inhibitor, liver regeneration in FGF-2-(-/-) mice was reduced significantly, whereas it remained unchanged in controls. CONCLUSIONS: Liver regeneration dynamics in FGF-2-(-/-) mice were comparable with controls, potentially due to a functional substitution of FGF-2 by VEGF.

Angiogenesis Inhibitors↗
PubMed2005

Expression of the sulfhydryl oxidase ALR (Augmenter of Liver Regeneration) in adult rat brain.

Mammalian Augmenter of Liver Regeneration protein (ALR) was first identified as a secondary growth factor involved in liver regeneration. Its sulfhydryl oxidase activity and involvement in iron homeostasis have been recently demonstrated. ALR is expressed in a broad range of peripheral organs, and initial experiments gave also evidence for the occurrence of this protein in brain. In the present study, we investigated in detail the expression of ALR in rat brain sections and determined its cellular and subcellular localizations using biomolecular and immunohistochemical procedures. As shown by Northern blot, ALR is differentially expressed throughout the rat brain, with the highest mRNA levels in the cerebellum and diencephalon. High protein levels were also detected in the brain and cerebellum by Western blot. ALR immunoreactivity was found in neurons and glial cells throughout brain rostrocaudal extent. Labeled astrocytes were particularly abundant in the white matter, and immunoreactive neurons were observed in several regions including the olfactory bulb, isocortex, hippocampal formation, amygdala, thalamus, hypothalamus, some nuclei of the brainstem and cerebellum. In neurons, immunoelectron microscopy showed the protein in the nucleus and mainly in mitochondria. These subcellular localizations may correlate with the occurrence of two ALR protein isoforms in the brain. In the central nervous system, the enzyme might be of importance in heavy metal homeostasis whose dysregulation can induce neurodegenerative disorders.

Animals↗
PubMed2003

The role of bone marrow stem cells in liver regeneration.

Hepatic oval cells involved in some forms of liver regeneration express many markers also found on hematopoietic stem cells (HSCs). In addition, multiple independent reports have demonstrated that bone marrow cells can give rise to several hepatic epithelial cell types, including oval cells, hepatocytes, and duct epithelium. These observations have resulted in the hypothesis that bone marrow resident stem cells, specifically HSCs, are an important source for liver epithelial cell replacement, particularly during chronic injury. The function of such stem cells in hepatic injury responses is the topic of this article. Taken together, the published data on the role of bone marrow stem cells in liver damage suggest that they do not play a significant physiological role in the replacement of epithelial cells in any known form of hepatic injury. Fully functional bone marrow-derived hepatocytes exist but are extremely rare and are generated by cell fusion, not stem cell differentiation. Nonetheless, bone marrow-derived cells may play important indirect roles in liver regeneration. First, they may serve as a source for the replacement of endothelial cells. Second, hematopoietic cells, including lymphocytes, neutrophils, macrophages, and platelets, may provide crucial factors required for efficient healing of damaged liver.

Animals↗
PubMed1996

Alterations in mRNA stability during rat liver regeneration.

We examined the in vivo transcriptional and posttranscriptional regulation of various genes involved in hepatocyte growth and replication that exhibited changes in steady-state mRNA levels after 70% partial hepatectomy (PH). Of the 19 genes examined by nuclear run-on assay, 17 demonstrated no change in transcriptional activity through the first 96 h of regeneration. However, results from in vivo half-life determinations indicated that changes in mRNA stability played a critical role in regulating transcript levels during liver regeneration. For many of the genes, alterations in transcript abundance correlated with similar changes in mRNA half-lives. Inhibition of protein synthesis by cycloheximide was generally associated with increased levels of mRNA expression, but no detectable changes in transcriptional rates in both control and regenerating rat liver. Finally, genomic methylation status was investigated by Southern analysis for several genes that displayed changes in mRNA stability. Interestingly, increases in mRNA half-lives for the genes p53, c-myc, H-ras, and ornithine decarboxylase were associated with decreased genomic methylation. In conclusion, regulation of gene expression beyond the immediate early phase of te cell cycle during rat liver regeneration after PH occurs predominantly at the posttranscriptional level. mRNA stability appears to be a significant factor in this control, and may itself be modulated by the methylation status of the corresponding genomic DNA.

Animals↗
PubMed1984

Pulsed electromagnetic fields increase the rate of rat liver regeneration after partial hepatectomy.

Pulsed extremely low-frequency electromagnetic fields interact with rat liver regeneration following partial hepatectomy when delivered to the rats immediately after the operation and every 12 hr thereafter. This interaction results first in an increased ornithine decarboxylase activity, an enzyme used as an early marker of cell growth. The rate of labeled thymidine incorporation into DNA is also increased by the treatments with magnetic fields during the early phases of liver regeneration. Glycogen depletion and lipid accumulation, two well-known early peculiar phenomena of liver regeneration following partial hepatectomy, are quantitatively decreased by the treatments with electromagnetic fields. The recovery to normal glycogen and lipid contents is completed within 5 days after surgery, instead of 7 days as found in control rats.

Animals↗