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PubMed2000

Differential association of p21Cip1 and p27Kip1 with cyclin E-CDK2 during rat liver regeneration.

BACKGROUND/AIMS: The cell cycle inhibitors p21Cip1 and p27Kip1 regulate liver regeneration by modulating the activity of cyclin-dependent kinases (CDKs). However, the specific role of these inhibitors in the regulation of CDK2 activity during liver regeneration remains unknown. The aim of this study was to examine the association of p21Cip1 and p27Kip1 with cyclin E-CDK2 and cyclin A-CDK2 complexes during rat liver regeneration and to correlate the association of both inhibitors with CDK2 activity. METHODS: The association of p21Cip1 or p27Kip1 with cyclin E-CDK2 or cyclin A-CDK2 and the activities of these complexes were analyzed by immunoprecipitation of rat liver homogenates obtained at different times after a partial hepatectomy (PH), followed by Western blotting or kinase assays. RESULTS: High amounts of p27Kip1 bound to cyclin E-CDK2 were observed during the first 13 h after PH, when CDK2 activity was very low. At 24 h, when CDK2 activity was maximal, the amount of bound-p27Kip1 decreased strongly. The amount of p21Cip1 bound to these complexes was low during the first 13 h but subsequently increased. No cyclin A-CDK2 complexes were found during the first 13 h after PH. At 24 h, complexes containing low levels of both inhibitors were detected and at 28 h, a significant increase in p21Cip1 and p27Kip1 associated with cyclin A-CDK2 was observed. CONCLUSIONS: p27Kip1 acts as a brake on cyclin E-CDK2 activity during the first 13 h after a PH. Both p21Cip1 and p27Kip1 down-regulate cyclin A-CDK2 activity at 28 h after PH, after its maximal activation.

Animals↗
PubMed2002

[Expression and relocation of B23 in the process of rat liver cell hyperplasia and liver regeneration].

OBJECTIVE: To study the B23 expression and relocation in the process of liver regeneration at different time periods after partial hepatectomy (PH) on healthy rats, and to study the feasibility of using B23 as a proliferation marker. METHODS: Eighteen rats underwent partial hepatectomy (PH). The regenerative liver tissues were obtained at day 1, 2, 3, 4,and 7 after PH. The expression of B23 in hepatocytes of the regenerative tissues was measured using monoclonal antibody against nucleophosmin/B23 by Western blot and immunohistochemistry. The expression of proliferate cell nuclear antigen (PCNA) in these cells were measured using monoclonal antibody against PCNA by both methods for comparison with that of B23. RESULTS: Expression of B23 in the steady state of liver cells before PH was hardly detected by both methods. The increased expression of B23 in the regenerative liver cells was quantitatively changed like a parabolic curve at day 1 to days 7 after PH, with the peak expression of B23 at day 3 after PH. This quantitative variation of B23 expression was similar to that of PCNA expression. The variation of location of B23 in the regenerative liver cells was observed from nucleolus (G1-S phase) to nucleoplasm (S-G2 phase) and to cytoplasm and mitotic chromosome (M phase). CONCLUSION: B23 expression is quantitatively increased and moves in location in the process of liver regeneration after PH. B23 may be regarded as a proliferation marker in liver regeneration and liver cell hyperplasia.

Animals↗
PubMed1993

Expression of the c-met/hepatocyte growth factor receptor gene during rat liver regeneration induced by carbon tetrachloride.

The hepatocyte growth factor is closely related to liver regeneration. And the c-met protooncogene is reported to encode a hepatocyte growth factor receptor. Little is known, however, about how the c-met gene is activated during liver regeneration. In this study, we demonstrated that expression of the c-met gene/hepatocyte growth factor gene was enhanced, with a distinct peak, following carbon tetrachloride administration, i.e., the gene expression was activated at 6 hours after the treatment, then decreased, and again increased. The present study suggested that this gene could be responding to liver regeneration and that the hepatocyte growth factor receptor plays an important role in regulating cell cycle progression prior to elevation of deoxynucleic acid synthesis during liver regeneration.

Animals↗
PubMed2006

Changes in growth factor and cytokine expression in biliary obstructed rat liver and their relationship with delayed liver regeneration after partial hepatectomy.

AIM: To study the effects of obstructive jaundice on liver regeneration after partial hepatectomy. METHODS: Hepatocyte growth factor (HGF), its receptor, c-Met, vascular endothelial growth factor (VEGF) and transforming growth factor-beta1 (TGF-beta1) mRNA expression in both liver tissue and isolated liver cells were investigated after biliary obstruction (BO) by quantitative reverse-transcription polymerase chain reaction (RT-PCR) using a LightCycler. Immunohistochemical staining for desmin and alpha-smooth muscle actin (alpha-SMA) was also studied. Regenerating liver weight and proliferating cell nuclear antigen (PCNA) labeling index, and growth factor expression were then evaluated after 70% hepatectomy with concomitant internal biliary drainage in BO rats or sham-operated rats. RESULTS: Hepatic TGF-beta1 mRNA levels increased significantly 14 days after BO, and further increased with duration of cholestasis. Meanwhile, HGF and VEGF tended to increase, but was not significant. In cell isolates, TGF-beta1 mRNA was found mainly in the hepatic stellate cell (HSC) fraction. Immunohistochemical studies revealed an increased number of HSCs (desmin-positive cells) and activated HSCs (alpha-SMA-positive cells) in portal areas after BO. In a hepatectomy model, liver regeneration was delayed in BO rats, as compared to sham-operated rats. TGF-beta1 mRNA was significantly up-regulated up to 48 h after hepatectomy, and the earlier HGF mRNA peak was lost in BO rats. CONCLUSION: BO induces HSCs proliferation and activation, leading to up-regulation of TGF-beta1 mRNA and suppression of HGF mRNA in livers. These altered expression patterns may be strongly involved in delayed liver regeneration after hepatectomy with obstructive jaundice.

Actins↗
PubMedDate not supplied

Hepatocyte and Kupffer cell functions during liver regeneration in streptozotocin-diabetic rats.

The insulinoprivic influence of acute severe streptozotocin diabetes on liver regeneration in rats was evaluated by determining liver weights as well as hepatocyte and Kupffer cell functional capacities. Functional capacities were assessed by bromosulfophthalein uptake for hepatocytes and carbon phagocytosis for Kupffer cells. Evaluation immediately after partial hepatectomy revealed a 66% reduction of liver mass, a 63% decrease in hepatocyte bromosulfophthalein removal, and a 65% decline in Kupffer cell carbon phagocytosis. Per cent recovery at 48-hr posthepatectomy was considerably greater for carbon phagocytosis than for bromosulfophthalein removal by regenerating livers. This apparent difference in functional recovery was likely due in part to enhanced non-Kupffer cell carbon phagocytosis. No significant differences of the three regeneration indices were noted for untreated streptozotocin-diabetic rats compared to nondiabetic animals. However, insulin administration to fasted streptozotocin diabetics significantly stimulated liver regeneration above that of untreated fasted rats and almost equivalent to that of pair-fed animals. Fasted rats had in general slower liver regeneration than pair-fed animals as expected. Furthermore, insulin administration to fasted nondiabetic rats after partial hepatectomy caused severe hypoglycemia and resulted in a further depression of liver regeneration.

Animals↗
PubMed1989

[Metabolic changes in liver tissue damage and the effect of nutrition on liver regeneration].

The present work reviews basic changes occurring in metabolism of carbohydrates, lipids and amino acids of an organism with liver injury and after resection of 70% of liver tissue. On the background of mentioned changes, the effect of individual energetic substrates and amino acids on the course of liver regeneration is discussed. Literature data and our proper results allow us to preclude that administration of only carbohydrates is impeding liver recovery. According to our observation, the liver regeneration after partial hepatectomy as well as the restoration of toxically damaged liver tissue may be favorably enhanced by infusion of lipid emulsion (Intralipid). The infusion of balanced amino acid solution (8% Nutramin) rather depresses the development of liver regeneration. Parenteral administration of amino acid solution enriched with branched chain amino acids (valine, leucine, isoleucine) has a favorable effect on the onset of liver regeneration after partial hepatectomy compared with glucose and of commercial amino acid solution (8% Nutramin). Probable mechanisms of inhibitory effect of glucose and favorable action of lipid emulsion infusions as well as branched chain amino acids on the initiation of liver regeneration are discussed.

Amino Acids↗
PubMed1987

Folylpolyglutamate synthetase activity in regenerating rat liver.

Regenerating liver of hepatectomized rat showed marked changes in folylpolyglutamate pattern. The activity of folylpolyglutamate synthetase, investigated at various times after the operation, showed a slight increase at 12 h, reached its highest value at 36 h and, for all the time studied, remained at the upper level as compared with controls. These results may contribute to explain the higher incorporation in regenerating liver of 3H folic acid into folylpolyglutamates at a higher number of glutamate residues and is consistent with the hypothesis that the addition of glutamate represents a control step in folate coenzyme synthesis and consequently of one-carbon metabolism.

Animals↗
PubMed2000

Isolation and characterization of a novel liver-specific gene, hepassocin, upregulated during liver regeneration.

By differential cDNA cloning coupled with Xenopus oocyte expression screening, we isolated a cDNA encoding a novel protein, termed 'hepassocin', the expression of which is upregulated in the regenerating rat liver. The cDNA contained a single open reading frame encoding a protein of 314 amino acids (ca. 34 kDa), including 24 amino acids of signal sequence. The protein expressed from the cDNA in Verots cells had activity to stimulate DNA synthesis in primary rat hepatocytes and was of 66 kDa or 34 kDa, under non-reducing or reducing conditions, respectively. Using an affinity column conjugated with the antibody raised against a peptide in a hydrophilic region, we purified hepassocin from the rat liver: it had a DNA synthesis-stimulating activity in hepatocytes. The hepassocin obtained here was 66 kDa, and the 34 kDa protein obtained under reducing conditions contained five cysteine residues, indicating that hepassocin is active as a homodimer. Northern blot analysis revealed that hepassocin mRNA (1.4 kb in length) occurred only in the liver, and in situ hybridization studies revealed its presence in parenchymal hepatocytes but not in endothelial cells. Furthermore, the expression of hepassocin mRNA was upregulated during compensatory hyperplasia after partial hepatectomy and regeneration after galactosamine treatment in the rat liver. These results suggest that hepassocin plays an important role in stimulating liver cell growth, through an autocrine mechanism.

Amino Acid Sequence↗
PubMed1999

Augmentative effect of cyclosporin A on rat liver regeneration: influence on hepatocyte growth factor and transforming growth factor-beta(1).

We investigated the effect of cyclosporin A (CsA) on rat liver regeneration following partial hepatectomy with reference to cytokine production. Rats were divided into two groups: those without CsA pretreatment (group 1) and those with CsA pretreatment (group 2). Animals were given olive oil vehicle or CsA (10 mg/kg) dissolved in olive oil daily by gavage from 4 to 1 days before hepatectomy. The ratio of regenerating liver weight to initial body weight in group 2 was significantly higher than that in group 1 at 72 h. Although a peak 5-bromo-2-deoxyuridine labeling index was found at 24 h after hepatectomy in both groups, the peak value in the CsA-treated animals was significantly higher than in controls. In both groups, hepatocyte growth factor concentrations in both plasma and liver tissue showed maximal values at 12 h. Liver tissue values in group 2, however, were significantly higher from 1 to 12 h compared to group 1. Transforming growth factor-beta(1) (TGF-beta(1)) concentrations showed minimal serial changes in group 1, while those in liver tissue of group 2 rats were significantly lower than in group 1. Plasma TGF-beta(1) concentrations did not differ. These results suggest that upregulation of hepatic regeneration with CsA pretreatment might be attributed in part to changes in production of these mitogenic and mitoinhibitory cytokines.

Animals↗
PubMed1984

[CFUs of the normal and regenerating liver in the sexually mature mouse].

Functional properties of CFUs have been studied in intact and regenerating liver of mice. According to a number of properties (proliferative activity, character of colony growth) CFUs in the liver are similar to CFUs in the peripheral blood and, probably, make the same population. In the regenerating liver relative contents of CFUs 3-5 days after a partial resection is substantially increasing. Concentration of CFUs (endogenic) increases significantly also in a locally injured and regenerating lobe, comparing to the intact lobe that is in the same organ. The transplanted bone marrow CFUs prevail in number in the regenerating liver over the intact liver. It is concluded that increasing contents of CFUs in the regenerating liver depend mainly on its creased property to invade and/or to hold the extrahepatic CFUs.

Animals↗
PubMed1999

Intra- and extrahepatic leukocytes and cytokine mRNA expression during liver regeneration after partial hepatectomy in rats.

We investigated intra- and extrahepatic leukocytes during liver regeneration after a 70% partial hepatectomy in the rats using flow cytometry and RT-PCR for cytokine mRNA expression. Our study indicated that LFA-1 CD3+ cell, NK3.2.3++ T cells, and CD5+ B cells, which are activated in autoimmune diseases and malignancy in humans and mice, were activated in the early phase of liver regeneration in the liver and the blood after partial hepatectomy in the rats. On measuring cytokine mRNA expression by RT-PCR, only IFN-gamma mRNA was detected in the normal rat liver. IFN-gamma mRNA expression clearly decreased in the liver on day 1 after partial hepatectomy and increased thereafter. IL-2 and IL-4 mRNA were not detected in the liver regardless of hepatectomy. Every cytokine was detected in normal spleen and increased in the early phase after partial hepatectomy. These were also detected in normal thymus; however, IL-2 and IFN-gamma mRNA expressions decreased and IL-4 mRNA expression increased slightly in the early phase after partial hepatectomy. Thus, the immune system dramatically changed both in the liver and elsewhere in the early phase of liver regeneration after partial hepatectomy.

Animals↗
PubMed2001

Anti-transforming growth factor-beta1 antibody transiently enhances DNA synthesis during liver regeneration after partial hepatectomy in rats.

The regulation of liver regeneration after partial hepatectomy (PHx) is complex and involves many different cytokines. We investigated the role of one of these, transforming growth factor-beta1 (TGF-beta1), an inhibitor of liver regeneration, in a Wistar male rat model, in which anti-TGF-beta1 antibody was injected immediately or 24 h after 70% PHx. Livers from treated animals contained an increased number of cells in S phase, according to 5-bromo-2'-deoxyuridine (BrdU) labeling 36 h after PHx. Antibody administration 24 h after PHx resulted in the highest peak of proliferation; moreover, peak MIB-5 labeling was also observed at that time. However, neither residual liver-weight-to-body-weight ratios nor regeneration rates differed significantly between any of the animals. Therefore, we also measured levels of serum TGF-beta1 and hepatocyte growth factor (HGF; an activator). With antibody administration at 0 or 24 h, TGF-beta1 levels were diminished at 24 or 36 h as compared with levels in control rats, but then rebounded, reaching a delayed peak at 48 or 72 h after PHx, respectively. Interestingly, there were also similar trends in HGF levels. These results indicate that TGF-beta1 may inhibit the G1 checkpoint, and serum TGF-beta1 concentration may influence HGF to regulate liver regeneration and to maintain homeostasis of proliferation after PHx.

Analysis of Variance↗
PubMed1984

Bile secretion in regenerating liver--a comparison of hepatic resection and ligation of the portal vein branch in dogs.

To elucidate the mechanism of bile secretion in the regenerating liver, changes of bile secretion were investigated in dogs during 12 weeks or more after 70% hepatectomy and after ligation of the portal vein branch supplying 70% of the area of the liver. The remnant liver weight increased remarkably and reached a normal level at 2 weeks after 70% hepatectomy. Liver weight increased in the nonligated lobes and decreased in the ligated lobes after ligation of the portal vein branch, but the whole liver weight was unchanged. Bile flow increased and continued for 12 weeks or more in the remnant liver except for a period of 2 weeks in the nonligated lobes. It decreased markedly in the ligated lobes. The taurocholic acid-independent bile flow was higher in the remnant liver than in nonligated lobes in both of which it was higher than normal liver. In the ligated lobes, taurocholic acid-independent bile flow was lower and taurocholic acid-dependent bile flow was higher than normal liver. When gallbladder bile was infused into the terminal ileum, bile flow increased in both the remnant liver and the nonligated lobes, except for 2 weeks in the remnant liver. Therefore it is suggested that in the regenerating liver enterohepatic circulation of bile acid and the new balance of the bile acid pool size participates in not only in bile flow but also in liver regeneration.

Animals↗
PubMed1979

[Oxidative phosphorylation in the intact and regenerating liver from a chronobiological viewpoint].

The dynamics of oxidative phosphorylation of the regenerating liver mitochondria on the endogenous and exogenous (glutamate, succinate, ascorbate) substrates in comparison with the normal diurnal and seasonal changes of this process was studied by the polarographical method. With the increase of its activity reflecting the deviation from the state of physiological rest (intact liver in spring, autumn, winter; regenerating liver), the range and synphasing of the oxidative phosphorylation indices were decreased, their bimodal distributions were transformed into the monomodal ones down to the full loss of diurnal periodicity. The degree of the process desynchronization depends, thus, directly on the degree of its activity.

Animals↗
PubMed1995

Role of heparin-binding epidermal growth factor-like growth factor as a hepatotrophic factor in rat liver regeneration after partial hepatectomy.

Several growth factors including hepatocyte growth factor (HGF) have been implicated in the regulation of liver regeneration. Recently, we reported that heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) has hepatotrophic effects in vitro. We investigated the role of HB-EGF as a hepatotrophic factor in regenerating rat liver after 70% partial hepatectomy. The level of HB-EGF messenger RNA (mRNA) in regenerating rat liver increased 1.5 hours after partial hepatectomy and reached a maximum (about sevenfold over normal) at 6 hours. In contrast, hepatic HGF mRNA levels increased at 12 hours and achieved maximal expression at 24 hours. HB-EGF protein expression increased about 2.8-fold over normal at 10 hours after partial hepatectomy. The number of EGF receptors, to which HB-EGF binds, decreased 6 hours after partial hepatectomy. HB-EGF mRNA levels increased in nonparenchymal cells (NPCs) at 6 hours after partial hepatectomy but not in hepatocytes. Using the reverse transcription-polymerase chain reaction (RT-PCR), HB-EGF gene expression was increased predominantly in Kupffer cells and sinusoidal endothelial cells but not in lipocytes and hepatocytes. These results indicated that HB-EGF may be an important growth factor, produced in an earlier phase rather than HGF, in the regenerating liver after partial hepatectomy by a paracrine mechanism.

Animals↗
PubMed2007

Animal models for the study of liver regeneration: role of nitric oxide and prostaglandins.

The mechanisms that permit adult tissues to regenerate are the object of intense study. Liver regeneration is a research area of considerable interest both from pathological and from physiological perspectives. One of the best models of the regenerative process is the two-thirds partial hepatectomy (PH). After PH, the remnant liver starts a series of timed responses that first favor cell growth and then halts hepatocyte proliferation once liver function is fully restored. The mechanisms regulating this process are complex and involve many cellular events. Initiation of liver regeneration requires the injury-related cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6), and involves the activation of cytokine-regulated transcription factors such as NF-kappaB and STAT3. An important event that takes place in the hours immediately after PH is the induction of nitric oxide synthase 2 (NOS-2) and cyclooxygenase 2 (COX-2), and the consequent release of nitric oxide (NO) and prostaglandins (PGs). NO is involved in the vascular readaptation after PH, favoring a general permeability to growth factors throughout the organ. This review examines the mechanisms that regulate NO release during liver regeneration and the animal models used to identify these pathways.

Animals↗
PubMed1990

Uptake of thymidine labeled on carbon 2: a potential index of liver regeneration by positron emission tomography.

Noninvasive measurement of liver regeneration with positron emission tomography has been attempted with 11C-thymidine; however, results were unsatisfactory using thymidine labeled on its methyl group. To evaluate whether the specificity of the method could be improved by modifying the labeling position of the tracer, thymidine labeled on its methyl group with 3H and thymidine labeled on its carbon 2 with 14C were injected in 22 hepatectomized rats either 1 hr (when DNA synthesis is not increased) or 24 hr after the surgical procedure (when the rate of DNA synthesis is maximal). Liver samples taken 10, 30 and 120 min after injection showed that, in contrast to 3H-radioactivity, 14C-radioactivity measured in whole tissue allowed a clear discrimination between regenerating and nonregenerating livers. In addition, 14C-radioactivity measured in whole tissue of regenerating livers correlated with the DNA radioactivity 10, 30 and 120 min after injection of the tracer. In contrast, no such correlation was found with the methyl-labeled thymidine. Analysis of the radioactive material present in the non-DNA fraction using ion exchange disks and high-performance liquid chromatography showed that 2-C-labeled thymidine was incorporated into DNA without accumulation of labeled metabolites whereas, for the methyl-labeled thymidine, almost all radioactivity was related to degradative products. Therefore the evaluation of the liver regeneration with the 2-C-labeled thymidine, which does not require cellular fractionation, should be suited for noninvasive measurement with positron emission tomography.

Animals↗
PubMed1992

Stimulatory effect of epidermal growth factor on liver regeneration after partial hepatectomy in rats.

The effect of epidermal growth factor (EGF) on liver regeneration was investigated in rats subjected to partial hepatectomy. In a dose-response study EGF in doses of 6 and 24 nmol/kg x day increased liver regeneration after treatment for 48 h compared with controls, whereas a dose of 48 nmol/kg x day had no effect. In a subsequent study EGF, 6 nmol/kg x day, accelerated liver regeneration significantly after 36, 48, and 72 h of treatment. A possible influence of EGF on other hepatotrophic factors was investigated. No changes in the concentration of gastrin, insulin, or glucagon was found in portal venous blood. This study has shown that EGF in small doses can stimulate liver regeneration, whereas higher doses are ineffective. The study suggests that EGF should be regarded as a hepatotrophic factor.

Animals↗