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PubMed1997

Serial ultrasound-guided percutaneous liver biopsy in a partial hepatectomy porcine model: a new technique in the study of liver regeneration.

UNLABELLED: Studies on liver regeneration are often carried out on small animal models such as the rat. The use of large animal models however has many advantages. Repeated biopsies of the liver may be carried out and the animal can thus serve as its own control. Sequential changes in the regenerative response to various putative hepatotrophic factors can therefore be studied. Ultrasound-guided percutaneous biopsy (USGPB) of the liver, a technique widely used in clinical practice to obtain liver samples, offers a means for repeated liver biopsies. This study was carried out to validate the use of serial USGPB of the liver as a research technique in the study of liver regeneration in a porcine hepatectomy model. MATERIAL AND METHOD: Left hepatectomy was carried out in nine Yorkshire pigs (20-30 kg). Bromodeoxyuridine (BrdU) at 50 mg/ kg BW was administered daily for the first 5 days after surgery. USGPB was carried out 1 hr later using 16F biopsy needles in a Biopty device. Ultrasonography was carried out using an Acuson XP10 color doppler ultrasound machine. Immunoperoxidase staining of the biopsy specimens was performed using mouse monoclonal antibody to BrdU. Regenerating cells were identified and labeling indices constructed for each day after hepatectomy. All animals were sacrificed at the end of the study and postmortem was performed. RESULTS AND CONCLUSION: USGPB was successful at every attempt and no animal suffered complications following the procedure. Median cumulative labeling indices increased rapidly after hepatectomy and the steepest rise occurred between the third and fourth day after surgery when it increased from 2.25 to 3.40% before leveling off. These results are consistent with those obtained by other reported techniques. USGPB of the liver overcomes the need for repeated laparotomies to obtain biopsy samples in a large animal model and has no morbidity and mortality that could lead to animal wastage.

Animals↗
PubMed1989

[The effect of hypophysectomy on liver regeneration in the rat].

Liver regeneration after partial hepatectomy in Wistar rats, hypophysectomised and otherwise has been studied. In almost all hypophysectomised rats, the regenerative processes were much less evident than in the non-hypophysectomised controls; only some hypophysectomised animals showed effective liver regeneration through an as yet unclear mechanism.

Animals↗
PubMed1996

Liver regeneration in health and disease.

Liver regeneration following partial hepatectomy results in proliferation of virtually all of the cells in the remnant liver, leading to restitution of mass within a few days. The regenerating liver maintains its functional capacity, and liver-specific factors, such as C/EBP's, continue to be expressed. Growth-induced transcription factors Stat3 and NF-KB regulate the expression of growth-response genes, ultimately leading to cell growth. Although well-modulated levels of cytokines may promote liver regeneration posthepatectomy, aberrant production of cytokines that can be seen in hepatitis, cirrhosis, and after liver transplantation may lead to hepatomas, fibrosis, and liver failure.

Acute-Phase Reaction↗
PubMed1988

Transforming growth factor beta mRNA increases during liver regeneration: a possible paracrine mechanism of growth regulation.

Transforming growth factor beta (TGF-beta) is a growth factor with multiple biological properties including stimulation and inhibition of cell proliferation. To determine whether TGF-beta is involved in hepatocyte growth responses in vivo, we measured the levels of TGF-beta mRNA in normal liver and during liver regeneration after partial hepatectomy in rats. TGF-beta mRNA increases in the regenerating liver and reaches a peak (about 8 times higher than basal levels) after the major wave of hepatocyte cell division and mitosis have taken place and after the peak expression of the ras protooncogenes. Although hepatocytes from normal and regenerating liver respond to TGF-beta, they do not synthesize TGF-beta mRNA. Instead, the message is present in liver nonparenchymal cells and is particularly abundant in cell fractions enriched for endothelial cells. TGF-beta inhibits epidermal growth factor-induced DNA synthesis in vitro in hepatocytes from normal or regenerating liver, although the dose-response curves vary according to the culture medium used. We conclude that TGF-beta may function as the effector of an inhibitory paracrine loop that is activated during liver regeneration, perhaps to prevent uncontrolled hepatocyte proliferation.

Animals↗
PubMed1995

Catalase-negative peroxisomes: transient appearance in rat hepatocytes during liver regeneration after partial hepatectomy.

Using light microscopy enzyme cytochemistry to localize catalase activity in peroxisomes, a population of peroxisome-negative hepatocytes was detected in livers of rats during liver regeneration induced by two-thirds partial hepatectomy. However, examination by electron microscopy revealed that this population of hepatocytes contained peroxisomes with a delimiting membrane and a nucleoid, but no cytochemically demonstrable catalase activity within their matrix. Regenerating livers 6, 18, 24, 36, 48 and 72 hours, and 1 week after partial hepatectomy showed hepatocytes without catalase activity. However, their numbers varied, with the most numerous appearing at 24 hours after partial hepatectomy. Mitosis of catalase-negative hepatocytes were seen along with mitosis of hepatocytes containing the normal complement of catalase-positive peroxisomes. The catalase-negative hepatocytes did not show evidence of apoptosis or necrotic cell death. Lysosomal acid phosphatase activity and bile canalicular ATPase activity were present in hepatocytes with catalase-negative peroxisomes. Another population of hepatocytes with a small number of catalase-positive peroxisomes appeared and were more numerous at 36 hours after partial hepatectomy; ultrastructurally, these hepatocytes contained both catalase-negative peroxisomes, which appeared to undergo dissolution, and catalase-positive peroxisomes, which were smaller in size. After complete restoration of the liver, all hepatocytes displayed essentially uniform numbers of catalase-positive peroxisomes. These studies indicated that during liver regeneration there is a transient loss of catalase in peroxisomes of some hepatocytes. These cells proliferate and with time acquire new catalase-positive peroxisomes. The observations are discussed in relation to peroxisome biogenesis, hepatocellular carcinogenesis, and oxidative stress during liver regeneration.

Animals↗
PubMed1992

Inhibition of increases in ornithine decarboxylase and putrescine has no effect on rat liver regeneration.

Polyamines are considered critical for cell proliferation. During liver regeneration in the rat, ornithine decarboxylase (ODC) mRNA and enzyme activity and polyamines (primarily putrescine and spermidine) are known to increase substantially. We examined the effect of inhibition of polyamine synthesis with alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of the ODC enzyme, on regenerating liver weight and total DNA, RNA, and protein, [3H]thymidine and [14C]leucine incorporation, number of mitotic figures, and putrescine, spermidine, and spermine contents. Rats received DFMO beginning 4 days before or immediately after two-thirds partial hepatectomy. In control rats, ODC activity, putrescine, and spermidine increased significantly during regeneration, whereas spermine was unchanged. In rats receiving DFMO, ODC and putrescine changed minimally but spermidine increased as usual. Spermine levels were modestly higher in rats receiving DFMO beginning 4 days before partial hepatectomy. However, despite ODC inhibition and substantially lower levels of putrescine, the course of liver regeneration in rats treated with DFMO was not affected. Total liver mass, DNA, RNA, and protein increased over 5 days equally in rats receiving DFMO and control rats. In addition, there were no differences in [3H]thymidine incorporation into DNA, [14C]leucine incorporation into protein or mitotic indexes between DFMO-treated and control rats at 24 and 48 h after partial hepatectomy. These results suggest that the well-known increases in ODC activity and polyamines that occur during regeneration are not required for liver to undergo its proliferative response to partial hepatectomy.

Animals↗
PubMed1986

Effect of splenectomy on liver regeneration and polyamine metabolism after partial hepatectomy.

The effect of splenectomy on hepatic ornithine decarboxylase (ODC) induction, DNA synthesis, and mitosis of hepatocytes was studied in rat liver after partial hepatectomy. ODC activity markedly increased in the early stages of liver regeneration, and the increase in the activity was significantly enhanced in splenectomized rats. Splenectomy specifically induced ODC since tyrosine aminotransferase and general protein synthesis were not affected. Splenectomy also enhanced increase in hepatic polyamines, DNA synthesis, and mitosis in regenerating liver. The results suggest that splenectomy affects liver regeneration after partial hepatectomy by enhancing induction of ODC activity, which is an important biochemical event in the early stage of liver regeneration.

Animals↗
PubMed1995

Down-regulation of c-myc mRNA after completion of liver regeneration in transgenic mice expressing hepatocyte growth factor in liver.

Hepatocyte growth factor (HGF) is the potent mitogen for liver parenchymal cells. It has been demonstrated that HGF enhances liver regeneration in transgenic mice which express HGF highly and exclusively in hepatocytes. In HGF transgenic mice where DNA synthesis of hepatocytes is active, c-myc is induced through an increased transcription rate by HGF. Therefore, expression of c-myc is up-regulated by HGF in this condition. However, relations between c-myc, HGF and cell growth still remain unclear. To clarify regulatory mechanisms of c-myc, we measured c-myc mRNA, HGF mRNA, proliferating nuclear antigen (PCNA) mRNA, PCNA protein and labeling index after a two thirds partial hepatectomy in livers from transgenic mice which express HGF in liver. We found that expression of c-myc mRNA was high on day 1 and day 3, and decreased drastically on day 5 when liver regeneration had completed in HGF transgenic mice (Shiota, et al., 1994). Levels of PCNA protein and labeling index on day 1 after liver regeneration were higher in HGF transgenic mice than those of normal siblings, but no differences were observed between HGF transgenic and wild type ]nice on day 3. Endogenous expression of HGF was observed only on day 1, although transgene expression was almost constant during liver regeneration. These data suggest that cell-to-cell contact is more important for regulation of c-myc than levels of HGF mRNA.

Animals↗
PubMed1994

Regulation of apo B mRNA expression in liver and intestine during liver regeneration induced by CCl4.

Acute liver damage in CCl4-treated rats is accompanied by a decrease of the lipoprotein particles HDL and VLDL. However, once the regenerative process has occurred both lipoproteins increase to values higher than control. In this study we have further analyzed the molecular mechanism involved in the induction of the hyperlipidemia during liver regeneration in rats treated with CCl4. The expression of apolipoprotein (apo) B gene at the apo B mRNA editing level has been analyzed during the regenerative process of the liver. The percent of apo B-48 and apo B-100 mRNA was determined and compared to the plasma levels of LDL and VLDL. These results confirm the existence of two different hyperlipidemic stages during liver regeneration. Total apo B mRNA is increased in liver and intestine during both hyperlipidemic stages. The ratio of apo B-100/apo B-48 mRNA remains constant during the first hyperlipidemic stage but the serum levels of VLDL are decreased. Then once the regenerative process has occurred, the steady-state levels of total apo B mRNA remaining, increased with higher amounts of apo B-100 than apo B-48. At this experimental time point the high levels of total apo B mRNA correlate with serum levels of VLDL that are significantly higher than control. These results indicate that apo B gene expression is induced at the mRNA level in liver and intestine during liver regeneration affecting the apo B mRNA editing mechanism in a complex manner and suggest further regulation at the translational or post-translational level.

Animals↗
PubMed1991

Influence of epidermal growth factor on liver regeneration after partial hepatectomy in mice.

The role of epidermal growth factor (EGF) in liver regeneration was studied in mice after partial hepatectomy. Two weeks before partial hepatectomy, mice were sham-operated (control) or sialoadenectomized (removal of submandibular glands) to reduce plasma EGF levels. Sialoadenectomized mice showed low plasma EGF levels (29.7 +/- 6.6 pmol/l; mean +/- S.E.M.) compared with controls (66.0 +/- 8.3 pmol/l). After partial hepatectomy, sialoadenectomized mice were treated with or without a daily s.c. injection of 5 micrograms EGF and the rate of DNA synthesis in the regenerating liver was monitored by [125I]iododeoxyuridine uptake. Control mice showed a sharp peak of DNA synthesis at 48 h after partial hepatectomy while sialoadenectomized mice showed a delayed and broad peak at 84 h. Treatment of sialoadenectomized mice with EGF (5 micrograms/mouse per day) completely restored the pattern of DNA synthesis so that a sharp peak appeared at 48 h. The total liver DNA content of the control mice (79.1 +/- 2.5% of the preoperative level; mean +/- S.E.M.) was significantly (P less than 0.01) higher than that of the sialoadenectomized mice (65.2 +/- 3.0%) 3 days after partial hepatectomy, but this difference disappeared on day 7 when liver regeneration was almost completed in both groups. Treatment of sialoadenectomized mice with EGF increased total liver DNA content (78.2 +/- 2.9%) to that of control mice on day 3 after partial hepatectomy. In addition, normal mice showed a rapid increase in plasma EGF levels at 1-8 h after partial hepatectomy, whereas sialoadenectomized mice showed low plasma EGF levels throughout the course of the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Molecular mechanisms of augmenter of liver regeneration as immunoregulator: its effect on interferon-gamma expression in rat liver.

BACKGROUND: We have shown that the administration of exogenous Augmenter of Liver Regeneration protein in intact rats i) regulates mitochondrial gene expression by inducing the transcription and translation of the nuclear-encoded mitochondrial transcription factor A, and ii) inhibits the lytic activity of liver-resident Natural Killer cells. AIMS: The present investigation was carried out to study the effect, in intact rats, of exogenous administration of Augmenter of Liver Regeneration protein on Interferon-gamma, a cytokine produced by activated Natural Killer cells and known to control the expression of mitochondrial transcription factor A, a nuclear gene responsible for mitochondrial metabolism. METHODS: Interferon-gamma was measured as messenger RNA in liver-derived mononuclear leukocytes and as protein in liver-derived Natural Killer cells after a single injection of Augmenter of Liver Regeneration protein. RESULTS: The data obtained demonstrate that: i) in intact rats, Augmenter of Liver Regeneration protein administration induces a reduction of Interferon-gamma in the liver-resident Natural Killer cells and ii) the administration of Interferon-gamma in 70% hepatectomized rats is followed by a significant reduction both of the mitochondrial transcription factor A expression and of liver regeneration. CONCLUSIONS: These data demonstrate the pivotal role of Augmenter of Liver Regeneration as Growth Factor and as immunoregulator by controlling, through Interferon-gamma levels, the mitochondrial transcription factor A expression and the lytic activity of liver-resident Natural Killer cells.

Animals↗
PubMed1970

Inner- and outer-membrane enzymes of mitochondria during liver regeneration.

1. Marker enzymes for the mitochondrial matrix, inner membrane, inter-membrane space and outer membrane were measured in mitochondria isolated from control and regenerating rat liver. The specific activity of these enzymes was then followed for up to 30 days after operation. 2. The specific activity of marker enzymes for the matrix, inner membrane and inter-membrane space remained constant during liver regeneration. 3. However, the specific activities of monoamine oxidase and kynurenine hydroxylase, both outer-membrane markers, fell by 67% and 49% respectively from their control values at 4 days after operation, and returned to normal by about 3 weeks. 4. The repression of kynurenine hydroxylase activity was shown to be unrelated to any independent variation in tryptophan catabolism, based on tryptophan pyrrolase assays. 5. These results are considered to indicate that enzymes of the inner and outer mitochondrial membranes are synthesized asynchronously during morphogenesis. 6. The enzyme complement of purified outer membrane at 4 days after operation was about 50% of that of the appropriate control. Thus the composition of the outer membrane itself may vary dramatically, and supports the concept that constitutive enzymes may turn over independently of a membrane's existence. 7. The behaviour of the rotenone-insensitive, NADH cytochrome c reductase did not parallel the other outer-membrane enzymes for intact mitochondria, but did so when assayed in highly purified fractions of outer membrane. This suggests a labile binding to the outer membrane during the early stages of morphogenesis. 8. Electrophoresis of inner- and outer-membrane proteins revealed little difference between control and experimental mitochondria at 4 days, except for an increase in several, high-molecular-weight components of the outer membrane. These bands closely correspond to similar bands derived from smooth endoplasmic reticulum. 9. The results are discussed in relation to the biogenesis and turnover of mitochondria, and are considered to provide evidence for turnover as a unit, at least for the matrix, inner membrane, inter-membrane space and possibly some form of primary outer membrane.

Animals↗
PubMed2005

Liver regeneration.

This review summarizes the functional aspects, cellular kinetics and molecular mechanisms related to liver regeneration. Liver regeneration is a model of regenerative growth of tissues in adult animals. Rapid biochemical and gene expression changes following initiation of regeneration are mediated by specific stimuli, including growth factors and cytokines. The whole process involves multiple feedback loops between same or different types of cells. The end result is restoration of hepatic mass and preservation of the normal histology of the liver. All of this complex phenomenology occurs while the liver continues to provide all the metabolic support required to sustain life of the organism.

Adaptation, Physiological↗
PubMedDate not supplied

Interleukin-6 augments hepatocyte growth factor-induced liver regeneration; involvement of STAT3 activation.

BACKGROUND/AIMS: In liver regeneration, quiescent hepatocytes need to be primed before they can fully respond to growth factors such as hepatocyte growth factor (HGF). Recently, interleukin-6 (IL-6) has been shown to play an important role in initiating liver regeneration via activating signal transducer and activator of transcription 3 (STAT3). We therefore investigated the effect of IL-6 on liver regeneration and examined STAT3 activation following IL-6 and/or HGF treatment in rats. METHODOLOGY: The animals underwent portal branch ligation (PBL) of the left lateral and median branches. They were intravenously treated with either IL-6 (500 microg/kg), HGF (50 microg/kg), both, or vehicle alone on and every 12 h after PBL. The degree of compensatory hypertrophy in unoccluded lobes was examined by measuring the wet weight ratios of the unoccluded lobes to the whole liver and the 5-bromo-2'-deoxyuridine labeling index of hepatocytes in each group. STAT3 expression in regenerating liver was examined by Western blotting and immunohistochemistry. RESULTS: Coadministration of IL-6 and HGF most effectively increased both the wet weight of the unoccluded lobes and the hepatocellular DNA synthesis. HGF as well as IL-6-treated animals showed moderate STAT3 activation in hepatocytes throughout the experiment. CONCLUSIONS: IL-6 augmented HGF-induced liver regeneration and hepatocellular replication. Liver regeneration stimulated by HGF treatment may be closely involved with STAT3 activation in a different manner induced by IL-6 treatment.

Animals↗