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PubMed1988

[Experimental study on tumor growth in the regenerating liver].

The purpose of this study was to investigate the effect of liver regeneration on the growth of liver tumor. VX2 carcinoma was transplanted in the liver of New Zealand white rabbits, and 40% partial hepatectomy was performed. The following results were obtained. 1. After 40% partial hepatectomy VX2 carcinoma was transplanted in the remaining liver. Two weeks later, the tumor volume was larger in partially hepatectomized than in shamoperated rabbits (p less than 0.01). 2. When 40% hepatectomy of rabbits which carrying VX2 carcinoma transplanted 2 weeks previously was performed, the mitotic index of the tumor at 24 to 36 hours was significantly higher in hepatectomized than in sham-operated rabbits (p less than 0.02). At 24, 36, 48 hours after partial hepatectomy, the mitotic index of the hepatocytes of the hepatectomized group was significantly higher than that of sham-operated group (24 hrs.: p less than 0.005, 36 hrs.: p less than 0.01, 48 hrs.: p less than 0.005). 3. At 36 hours after partial hepatectomy there was a significant increase of DNA synthesis in tumor cells as compared with that in sham-operated controls (p less than 0.05). These data indicate that liver regeneration enhances the tumor growth in regenerating liver.

Animals↗
PubMed1986

Effects of liver regeneration on tRNA contents and aminoacyl-tRNA synthetase activities and sedimentation patterns.

The tRNA content and aminoacyl-tRNA synthetases of regenerating liver in the phase of rapid growth were compared with those of livers from both intact and sham-operated rats. At 48 h after hepatectomy, the amount of active tRNA (called 'total acceptor capacity') is significantly higher in regenerating liver than in control livers, owing to a general, possibly not uniform, increase in the various tRNA families, which suggests that it may contribute to the increased protein synthesis and to decreased protein degradation as well. The activities of most, but not of all, aminoacyl-tRNA synthetases in cell sap of regenerating liver tend to be greater than normal. Increased activity of histidyl-tRNA synthetase fits in with the possibility that the mechanisms that control the rate of protein degradation through aminoacylation of tRNAHis in cultured cells [Scornik (1983) J. Biol. Chem. 258, 882-886] also operate in the liver and play a role in regeneration. Sedimentation analysis of cell sap in sucrose density gradients shows a shift of prolyl-tRNA synthetase activity toward the high-Mr form in regenerating liver. This change might be related to the positive protein balance and to growth in vivo, since it is also observed in the anaplastic Yoshida ascites hepatoma AH 130.

Amino Acids↗
PubMed1988

The stimulating effect of a cytosol extract from regenerating liver on isolated hepatocytes and the positive role of insulin.

Several kinds of damage induce a regenerative response in the liver. Partial hepatectomy is a well known method, suitable for studying liver regeneration and factor/s involved in it. The presence of the so called Hepatic Stimulator Substance has been demonstrated in the cytosol obtained from regenerating hepatocytes, and it has been partially characterized, from a molecular point of view. Mainly, it stimulates liver regeneration and Tritiated Thymidine incorporation in cultured hepatocytes as demonstrated in this paper (Control Hepatocytes: 8447 +/- 660.4 cpm, (mean +/- sd), Test Hepatocytes: 16974 +/- 2720.9 cpm; Index of Stimulation: 2.01). Furthermore, the stimulating activity of HSS is increased by the presence, in the culture media, of insulin which has been proved to have a positive role in liver regeneration (Control Hepatocytes: 8889 +/- 367.3 cpm; Test Hepatocytes: 21588.5 +/- 1232.4 cpm; Index of Stimulation: 2.42, p less than 0.05). These data seem to suggest that liver is probably the site of production/activity and action of factor/s that stimulate/s liver regeneration; but other substances exist, such as insulin, which play a permissive role.

Animals↗
PubMed1987

Translocation of epidermal growth factor to the hepatocyte nucleus during rat liver regeneration.

To determine the fate of exogenous epidermal growth factor (EGF) in regenerating liver, 125I-labeled EGF was injected into rat portal veins at various times after 70% hepatectomy. Epidermal growth factor was taken up by the liver remnant at all time points studied (0, 4, 8, 16, and 36 h), but at 8 h after hepatectomy a large quantity was retained by the liver and EGF degradation products appearing in the bile decreased markedly. Electron microscopic autoradiography of the regenerating livers 1 h after injection of 125I-EGF demonstrated that 27% of the grains were associated with hepatocyte nuclei compared to 0.5% in shamoperated controls. There was also a concomitant decrease in grains associated with the lysosomal compartment. Nuclei isolated from regenerating livers exposed to 125I-EGF also demonstrated a three-fold increase in radioactivity compared to nuclei from control livers. Nearly 70% of nuclear radioactivity was precipitable with a specific antibody to EGF, and a small fraction appeared to be part of a high molecular weight complex. These data support the hypothesis that during the pre-S phase of liver regeneration, EGF is translocated to the nucleus rather than to lysosomes, and may participate in the initiation of deoxyribonucleic acid synthesis or alteration of gene expression.

Animals↗
PubMed1987

Behavior of L-threonine-degrading enzymes during liver regeneration.

We examined the effects of a two-thirds hepatectomy in the adult rat on the activities of the three L-threonine-degrading enzymes, L-threonine dehydratase, L-threonine aldolase and L-threonine dehydrogenase. Noticeable variations were observed which did not occur in either sham-operated or turpentine-treated rats and were not linked to food intake. They were considered specific to the regenerating liver. When the reactions were followed in vitro, L-threonine deaminase and L-threonine aldolase were significantly lower for the first 12-24 h: L-threonine dehydrogenase decreased only after 48 h. These results are linked to a decrease in the enzyme concentration in the tissue. L-Serine and L-threonine liver concentrations increased 2-3-fold during the same periods. When the activities were evaluated in vivo, the levels of the first two enzymes remained constant for 24 h, but increased after 48 h; L-threonine dehydrogenase increased between 12 and 48 h. The in vivo activity of the enzymes was reflected by total L-threonine degradation, which had a single sharp peak at 48 h. The asynchronous variations in enzyme activity are related to the differences in protein metabolism which occur in the regenerating liver, and are the consequence of a new transient differential control. The changes observed are significant in liver regeneration; they regulate the consumption and the serum and liver levels of L-serine and L-threonine, setting them aside for protein synthesis. They minutely control the flux of amino acids toward gluconeogenesis, since, during the first 48 h after partial hepatectomy, the production of glucose is ensured principally by lactate; the contribution of L-threonine seems to be more significant only at 48 h. These findings are useful in the study of the regulation of the enzymes involved in amino acid metabolism during liver regeneration.

Alcohol Oxidoreductases↗
PubMed2006

Rapid induction and activation of Tec tyrosine kinase in liver regeneration.

BACKGROUND: Previous studies have indicated that Tec tyrosine kinase is differentially expressed in the regenerating liver. The purpose of the present study was to further investigate the potential involvement of Tec tyrosine kinase in hepatocyte proliferation and liver regeneration. METHODS: Tec kinase gene expression after partial (two-thirds) hepatectomy was examined by representational difference analysis. Tissue distribution and potential involvement of Tec kinase in liver regeneration and hepatocyte proliferation were then determined by northern blotting, reverse transcription-polymerase chain reaction (RT-PCR), and western blotting. Full-length rat Tec cDNA was cloned. RESULTS: Using this cDNA as the probe, northern blotting showed that Tec was specifically expressed in liver and kidney, the highest expression of Tec being detected in embryonic day 15-19 fetal livers. In contrast, the expression level of Tec in adult and neonatal rat livers was significantly decreased. Similar results were obtained from western blotting analyzes. It was thus hypothesized that Tec might be involved in hepatocyte proliferation. To test this hypothesis, Tec expression was examined in regenerating rat livers. An increase in Tec expression and activation of Tec kinase were observed within 1 h after partial hepatectomy. Moreover, it has been shown that hepatocyte growth factor (HGF) dramatically induces Tec expression in primary rat hepatocytes. Additionally, it was observed that Tec gene expression in serum-starved liver tumor cell line HepG2 was substantially decreased. Stimulation with 10% fetal bovine serum and insulin but not epidermal growth factor resulted in dramatic elevation of Tec expression in these cells. CONCLUSION: Tec is an inducible early response gene that might enhance hepatocyte proliferation and liver regeneration.

Animals↗
PubMed2005

Transcriptome analysis of rat liver regeneration in a model of oval hepatic stem cells.

We have performed serial analysis of gene expression of the regenerating liver. In the rat model of partial hepatectomy and 2-acetamidofluorene treatment liver regeneration recruits hepatic stem cells referred to as oval cells. We analyzed a total of 153,057 tags in livers from normal control (52,343 tags), from sham 2-acetamidofluorene-treated control (50,502 tags), and from the early stage of oval cell proliferation (50,212 tags). Comparative analysis of the three transcriptomes identified 27 up-regulated and 18 down-regulated genes. Real-time PCR analysis confirmed 11 temporally regulated genes that correlate with oval cell development. Interestingly, we found by Western blot protein analysis of regenerating livers that the cell cycle gene Cdc42 was induced concomitant with the proliferation marker cyclin D1 and the oval cell marker alpha-fetoprotein. Our studies provide new insights into the molecular mechanism of liver regeneration through oval cells.

2-Acetylaminofluorene↗
PubMed2006

[Analysis of changes about hsbp1, hsf1, hsf2 AND hsp70's expression levels in rat's regenerating liver].

Heat shock factor binding protein 1 (HSBP1), a recently discovered protein, weakens and blocks transcription of the heat shock protein 70 (HSP70) gene when binding to HSF1, but HSBP1 can promote cell growth, cell development and cell differentiation when binding to HSF2. Partial hepatectomy (PH) in rat creates injury stimulation and induces liver regeneration. How does hsbp1 coordinate two processes sequently is extremely interesting. This paper, based on cloning the full-length cDNA of hsbpl in rat, applied in situ hybridration and Rat Genome 230 2.0 Array to analyze hsbp1, hsf1, hsf2 and hsp70 expression in liver after PH and sham-operation. The results indicated that the hsbp1 expression level was down-regulated meaningfully at 0.5-2h and up-regulated meaningfully at 8-16h after sham-operation, while hsf2 expression level did not meaningfully change at 0-144h after sham-operation. hsbp1 expression level was up-regulated meaningfully at 6h and 66-144h,and hsf1 at 8-16h, hsf2 at 2-16h, hsp70 at 0.5-24h after PH. Our data suggested that up-regulated expression of the hsp70 at 0.5-12h after sham-operation was controlled by intracellular HSF1, and then controlled by hsbp1 down-regulated at 0.5-2h and hsf1 up-regulated at 8-16h. In the early phase of liver regeneration in rats, hsbp1 and hsf2 expression levels were up-regulated, which promoted cell proliferation through HSBP1 and HSF2 up-regulating,upa activating,c-jun enhancing, intracellular matrix (ECM) degradation, activating the hepatocyte-like growth factor (HGF) etc. In the late phase of liver regeneration (66-144h), hsbp1 expression level was up-regulated, which promoted reconstruction of liver structure and recovery of liver function through HSBP1 inhibiting hsp70 expression, up-regulating genes related to growth, development, differentiation. In conclusion, down-regulating of hsbp1 contributed to interaction between HSF1 and HSE,increased hsp70 expression and enhanced anti-injured capacity of liver and rats. HSBP1 and HSF2 activated the genes related to growth, development, differentiation and then promoted liver regeneration in rats.

Animals↗
PubMed2001

Changes in essential fatty acid patterns associated with normal liver regeneration and the progression of hepatocyte nodules in rat hepatocarcinogenesis.

Changes in lipid metabolism were monitored in rat hepatocyte nodules at certain time points over 9 months. Tissue obtained from partially hepatectomized rats, collected over a period of 7 days, were included as a control for normal hepatocyte cell proliferation. Two important features regarding the lipid profiles of hepatocyte nodules and normal regenerating liver were the increased concentrations of phosphatidylethanolamine (PE), resulting in a decreased phosphatidylcholine/phosphatidylethanolamine (PC/PE) ratio, and cholesterol. These changes coincided with increased membrane fluidity in the nodules and regenerating liver. With respect to the fatty acid (FA) profiles of the nodules, C18:1omega9 and C18:2omega6 increased in PE and PC whereas C20:4omega6 decreased in PC and increased in PE. C22:5omega6 and C22:6omega3, the end products of the omega6 and omega3 metabolic pathways, respectively, decreased in PC and remained unchanged in PE. The FA levels in PC reflected an impaired delta-6 desaturase enzyme, whereas this effect was masked in PE due to the increased concentration of this phospholipid fraction. In regenerating liver, the FA profiles of PC and PE showed the same pattern as described for the hepatocyte nodules, except for C18:1omega9 which decreased in PC and increased non-significantly in PE. The increased C18:1omega9 level, a FA with anti-oxidative properties, as well as the decreased levels of the long-chain polyunsaturated fatty acids (C20 and C22 carbon chains), have been associated with the decreased lipid peroxidation level in hepatocyte nodules. The resultant decrease in peroxidative metabolites, known to affect apoptosis, could be important in the progression of the nodules into neoplasia. The present results indicate that the altered lipid parameters associated with hepatocyte nodules closely mimics cellular proliferation in regenerating liver and could be responsible for the enhanced proliferation and/or altered growth pattern in these lesions. The altered FA profiles suggest various pathways in which FA could play a role in transmembrane signalling related to the altered cell proliferative and apoptotic pathways. The persistent changes in the hepatocyte nodules suggest that the lipid metabolism escapes the regulatory mechanisms required for normal cellular homeostasis at different levels.

Animals↗
PubMed1988

Inhibition of cytochrome P-450p (P450IIIA1) gene expression during liver regeneration from two-thirds hepatectomy in the rat.

Regenerating liver from partial hepatectomy (HPX) is known to exhibit a strong and transient deficiency in both spectrally detectable microsomal cytochrome P-450 (P-450) and related monooxygenase activities. Male Wistar rats (250-300 g) were HPX or sham operated and liver was excised at different times after operation. The time course of accumulation of five different forms of P-450 (including P-450b/e, P-450c, P-450d, P-450p and P-450UT-A) was determined in the regenerating liver, by Western blots developed with specific antibodies. With the exception of P-450c, whose level was not affected, the accumulation of other forms strongly decreased during the first 24 hr after HPX. For P-450b/e and P-450d, 80% of initial level was restored at 96 hr, whereas for P-450p and P-450UT-A, two major forms in control rat liver, the accumulation was only 20-25% of the initial, 1 week after HPX. No significant decrease was observed in sham operated animals. Plasmid pDex 12 containing a cDNA insert coding for P-450p was used to further investigate the effects of HPX on P-450p mRNA level and gene transcription. Northern blot analysis of RNA from regenerating liver (cDNA insert of pDex 12 being used as a probe) demonstrated that P-450p mRNA level decreased strongly to a minimum 12 hr after operation. This was correlated with a strong and transient decrease in P-450p gene transcription determined from nuclear run on experiments, the time course of which, however, did not account for the early decrease in mRNA level. We conclude that P-450p deficiency in the regenerating liver results from a combination of transient inhibition of gene transcription and early increase of mRNA degradation. Time course and amplitude of the decrease in P-450 UT-A accumulation suggest an inhibition of gene transcription as observed with P-450p.

Animals↗
PubMed1996

Selective enhancement of lipid peroxidation in plasma membrane in two experimental models of liver regeneration: partial hepatectomy and acute CC14 administration.

It has been proposed that lipid peroxidation (LP) might be a modulator of cell division, influencing initiation and cessation of mitosis in regenerating liver. However, the understanding of the participating role of this event in the onset of liver proliferation has been hampered by the fact that both higher or lower LP have been reported after two-thirds partial hepatectomy (PH). Therefore, the present study deals with the extent of LP in the main subcellular fractions from rat liver at early stages of regeneration, induced by either PH of 70% or acute CCl4 administration. Our results, using several methods to monitor LP, indicate a differential effect in the peroxidative pattern of specific subcellular fractions from regenerating liver after 24 hours of PH: a decrease in microsomes and an increase confined to plasma membrane and cytosolic fractions, peaking after 24 hours of PH. In CCl4-treated rats, higher LP was also noted in plasma membrane and cytosol, being maximal at the replicative stage in this experimental model (48 hours). In addition, increased LP was found in microsomal and nuclear fractions, declining before the 48 hours. In hepatectomized rats, changes in LP seem to be an organ-specific event and related to only PHs capable of triggering a synchronized proliferative response, namely above 40%. These results show that LP, promoted by PH and CCl4 administration, is qualitatively distinct among subcellular fractions and may indeed be a normal cell event of physiological importance in the regenerating liver.

Animals↗
PubMed2005

Normal liver regeneration and liver cell apoptosis after partial hepatectomy in tumor necrosis factor-alpha-deficient mice.

AIMS/BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is known as a proinflammatory cytokine that has been implicated as a contributing factor in a number of disease processes. TNF-alpha also influences liver repair following hepatotoxic damage, and regeneration following partial hepatectomy (PH). The aim of this study was to assess the mechanism by which TNF-alpha influences liver cell apoptosis and regeneration following PH in TNF-alpha-deficient (TNF-alpha(-/-)) mice. METHODS: PH was performed in wild mice and TNF-alpha(-/-) mice. RESULTS: In both groups, serum alanine aminotransferase and serum total bilirubin levels comparably peaked at 6 and 48 h after PH, respectively. No differences were observed in hepatocyte proliferation, as determined by mitotic and the proliferating cell nuclear antigen labeling indices, between TNF-alpha(+/+) and TNF-alpha(-/-) mice. Few terminal deoxynucleotidyl transferase nick end-labeling-positive hepatocytes were seen in either type of mice. Nuclear factor-kappa B DNA binding activity in the remaining liver of TNF-alpha(-/-) mice after PH was similar to that of control mice. Ribonuclease protection assay showed that transforming growth factor beta1 mRNA was up-regulated comparably in the livers of the two groups, and that other cytokines were hardly seen in either. Interleukin-6/ signal transducer and activator of transcription-3-dependent pathway was not affected in TNF-alpha(-/-) mice. CONCLUSIONS: These findings suggest that TNF-alpha has little influence on liver regeneration and liver cell apoptosis after PH in mice.

Alanine Transaminase↗
PubMed1996

Increase of mtDNA-binding proteins and mitochondrial mRNAs in regenerating liver.

In order to elucidate the mechanism of energy supply for liver regeneration after partial hepatectomy, we investigated mtDNA replication and transcription in regenerating rat liver. Changes of mtDNA-binding proteins, mtDNA, and mitochondrial mRNAs were monitored at 0, 12, 24, 48, 96, and 168 hr after the operation by gel mobility shift assay and Southern and Northern blot analyses, respectively. We focused on mtDNA-binding proteins specific for four different sequence elements possibly involved in regulation of mtDNA replication and transcription. Amounts of all the proteins sharply increased to maximum (4- to 10-fold of the preoperative level) 12 hr after partial hepatectomy and then decreased for 24 hr. After 24 hr, the amount of the respective binding protein changed diversely. Mitochondrial mRNA levels per gram tissue weight were unchanged during the first 12 hr after partial hepatectomy, but dramatically increased to maximum (4-fold) at 24 hr. In contrast, mtDNA content, expressed as a ratio of the nuclear cytochrome c1 gene, was unchanged during the first 48 hr and then started to increase, reaching maximum (1.5-fold) at 4 days. These results suggest that the energy supply in the early stage of the liver regeneration following hepatectomy is achieved mainly through enhancement of mtDNA transcription in which the mtDNA-binding proteins probably play regulatory roles.

Animals↗
PubMed1993

[Functional and morphological changes and liver regeneration after liver resection].

The dynamics of functional and morphological changes and regeneration of the liver were followed-up in 192 out of 202 patients who underwent operation with resection of the liver for its various focal lesions. The main biochemical indices in the absence of cirrhosis are normalized in 6-7 weeks after extensive resection and in 3-4 weeks after economical resection. In cirrhosis the volume of the organ is not restored completely and normalization of the biochemical indices is essentially delayed. After extensive resection the volume of the remaining liver increases (up to 100%) in the early postoperative period (three weeks) with subsequent gradual diminution (to one year) to the volume of the noninvolved hepatic parenchyma measured before the operation. Regeneration of the liver is activated sharply in the early postoperative period. Study of these changes showed that adequate and stable compensation of the functional condition of the liver occurs in 12-18 months after extensive resection and in 2-4 months after economical resection.

Adolescent↗
PubMed2001

Increased levels of forkhead box M1B transcription factor in transgenic mouse hepatocytes prevent age-related proliferation defects in regenerating liver.

The forkhead box (Fox) family of transcription factors share homology in the winged helix/forkhead DNA-binding domain and play important roles in regulating cellular proliferation, differentiation, longevity, and cellular transformation. Forkhead box M1B (FoxM1B) is a ubiquitously expressed member of the Fox transcription factor family whose expression is restricted to proliferating cells and that mediates hepatocyte entry into DNA synthesis and mitosis during liver regeneration. Recent cDNA microarray studies indicated that age-related defects in cellular proliferation are associated with diminished expression of the FoxM1B transcription factor. Here, we show that increased levels of FoxM1B in regenerating liver of old transgenic mice restore the sharp peaks in hepatocyte DNA replication and mitosis that are the hallmarks of young regenerating mouse liver. Restoration of the young regenerating liver phenotype is associated with increased expression of numerous cell cycle regulatory genes that include cyclin D1, cyclin A2, cyclin F, cyclin B1, cyclin B2, Cdc25B, and p55cdc. Cotransfection assays in the human hepatoma HepG2 cell line demonstrated that FoxM1B protein stimulated expression of both the cyclin B1 and cyclin D1 promoters, suggesting that these cyclin genes are a direct FoxM1B transcriptional target. These results suggest that FoxM1B controls the transcriptional network of genes that are essential for cell division and exit from mitosis. Our results indicate that reduced expression of the FoxM1B transcription factor contributes to the decline in cellular proliferation observed in the aging process.

Aging↗
PubMed2004

Angiogenesis inhibitor TNP-470 can suppress hepatocellular carcinoma growth without retarding liver regeneration after partial hepatectomy.

PURPOSE: We investigated the suppressive effect of the angiogenesis inhibitor TNP-470 on accelerated hepatocellular carcinoma (HCC) growth in the regenerating liver. METHODS: After 70% partial hepatectomy (PH), AH-130 cells were injected into the portal vein of Donryu rats. A control group was given the vehicle only, and the treated group was given 10 mg/kg TNP-470 subcutaneously every second day, from 24 h after tumor implantation, seven times. On day 14, tumor growth was evaluated by the number of foci on the liver surface, liver weight, and the microvessel density of the tumor. RESULTS: The number of foci was significantly less in the treated group (116.5 +/- 103.1) than in the control group (319.3 +/- 223.1) ( P < 0.05), as was microvessel density, which was 31.3 +/- 14.0/mm2 in the treated group and 61.2 +/- 18.9/mm2 in the control group ( P < 0.05). The liver tended to weigh less in the treated group (12.15 +/- 1.28 g) than in the control group (15.22 +/- 5.35 g). We also assessed whether TNP-470 retards liver regeneration. Seven days after 70% PH, the liver weight in the treated group was similar to that in the control group. Total bilirubin, serum glutamic oxaloacetic transaminase, and serum glutamic pyruvic transaminase were not higher in the treated group than in the control group. CONCLUSION: TNP-470 can suppress HCC growth without retarding liver regeneration after PH.

Angiogenesis Inhibitors↗