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PubMed1995

Distinct patterns of cyclin D1 regulation in models of liver regeneration and human liver.

The expression of cyclin D1 and associated cdks was examined in models of liver regeneration and human liver specimens. In mouse liver after 70% partial hepatectomy, there was > 20-fold induction of cyclin D1 mRNA and protein, beginning prior to peak DNA synthesis. In normal rat liver, basal levels of cyclin D1 protein were significantly higher than in the mouse. After hepatectomy in the rat, cyclin D1 mRNA was induced 6- to 10-fold, while the protein levels changed < 2-fold and did not parallel changes in the mRNA. Cyclin D1 protein was detected in freshly isolated rat hepatocytes, but this diminished within 6 hours in culture. After growth stimulation with HGF, cyclin D1 mRNA was induced 3- to 5-fold and its protein > 20-fold in rat hepatocytes. Immunoprecipitation of cyclin D1 demonstrated its association with cdk4 but not cdk5 in regenerating liver. In human liver biopsy specimens, cyclin D1 protein was detectable in normal liver and induced 2- to 10-fold in mitotically active liver following transplantation. These results suggest that the regulation of cyclin D1 protein in human liver may more closely parallel the mouse than the rat hepatectomy model. Furthermore, cyclin expression in primary cells in culture may differ significantly from that observed in vivo.

Animals↗
PubMed1982

Intracellular distribution of transglutaminase activity during rat liver regeneration.

Transglutaminase and ornithine decarboxylase activities have been assayed at intervals after partial hepatectomy in regenerating liver cells fractionated to obtain nuclear, cytoplasmic-particulate, and cytoplasmic-soluble fractions. Ornithine decarboxylase activity, localized entirely in the cytoplasmic fractions, undergoes a dramatic induction during the first 4 h after partial hepatectomy and remains elevated. This induction is very sensitive to inhibition by cycloheximide and actinomycin D, as previously reported. Transglutaminase activity is localized in both the cytoplasm and the nucleus with the highest specific activity in the nucleus. Nuclear transglutaminase activity approximately doubles in the first 2 h of liver regeneration, apparently as a result of a translocation of enzyme from the cytoplasm to the nucleus. Inhibitor studies indicate that the translocation is not dependent upon protein or RNA synthesis. In the first 2 h, actinomycin D slightly activates transglutaminase activity in the cytoplasmic-particulate and nuclear fractions. Only at 4 h after the onset of regeneration do actinomycin D and cycloheximide show some inhibition of transglutaminase activity indicating de novo synthesis at this time. A broad increase of transglutaminase activity occurs from hours 12-16 to hour 32 after partial hepatectomy in the nuclear and cytoplasmic-particulate fraction. These data suggest the existence of a function for transglutaminase in the nucleus of rat liver cells.

Acyltransferases↗
PubMed1981

Hyperinsulinemia and hyperglucagonemia in fasted rats during liver regeneration.

The two pancreatic hormones, insulin and glucagon, have been implicated as hepatotrophic factors for the regenerating liver after partial hepatectomy. Similar to previous studies, hyperglucagonemia and hypoinsulinemia were noted following major liver resection of initially well-fed rats. In contrast to well-fed animals, rats fasted for 24 h prior to surgery to deplete hepatic glycogen and establish low basal insulin levels developed both portal venous hyperglucagonemia and hyperinsulinemia after 67% hepatectomy. Elevation of basal portal venous levels of the two hormones suggested enhanced pancreatic secretion of insulin and glucagon in response to acute liver injury in fasted animals. Because polypeptide hormones must bind to specific hepatic cell membrane receptors to exert their hepatotrophic influences, basal portal-systemic venous differences of insulin and glucagon and glucose-elicited portal-hepatic venous insulin differences were evaluated. The evidence implies that hepatic extraction and, therefore, cell membrane receptor binding of both insulin and glucagon by regenerating livers were enhanced even though portal venous levels of the two hormones were elevated.

Animals↗
PubMed1980

[Some features of nuclear genome transcription at early stages of liver regeneration. Effect of cytoplasmic factors on the RNA-polymerase activity of isolated nuclei].

Cytosol from the regenerating liver significantly activates the RNA-polymerase activity of isolated nuclei in normal liver. This activation occurs immediately after partial hepatectomy, reaches its maximum after the 1st post-operative hour and is practically eliminated after 1,5 hrs. The effect is thermolabile and is completely blocked by a preliminary administration of cycloheximide. Fractionation of cytosol on DEAE-cellulose reveals significant chromatographic differences of the activating factor as compared to that described in literature, which is present both in normal and regenerating liver. An important role of this factor in reprogramming of the genome from the hepatocytes at the preproliferation stage is postulated.

Animals↗
PubMed1983

Inhibitory effect of cimetidine on liver regeneration after two-thirds hepatectomy in rats.

The effects of cimetidine on the regenerating liver were studied in rats after they had two-thirds hepatectomy. In Group I, standard two-thirds hepatectomy was performed. In Group II, cimetidine in a dose of 40 mg/kg was given intramuscularly immediately and 24 and 48 hours after two-thirds hepatectomy. In Group III, the same amount of cimetidine was given after a sham operation. Mortality rate, liver weight restoration, mitotic activities of remnant livers, and serum levels of aminotransferases and albumin were examined from 24 hours to 14 days after operation. The mortality rate was 11.1 percent in Group II, whereas no rats in Groups I and III died. Although there were no differences in the residual liver weights among the hepatectomized groups, treatment with cimetidine induced substantial suppression and delay of liver cell division. The serum aminotransferase levels in Group II increased significantly after hepatectomy compared with the levels in Group I. The albumin synthesis remained suppressed in Group II. Light microscopy showed prolonged liver steatosis and marked dilatation of the sinusoidal space in that group. Our results may indicate that cimetidine has an inhibitory effect on liver regeneration and that it should be administered very carefully after extensive hepatic resection if applied as prophylaxis for the life-threatening complication, stress ulcer syndrome. Otherwise, antacid therapy or other trials should be carried out.

Animals↗
PubMed1996

Use of an asialoglycoprotein receptor-targeted magnetic resonance contrast agent to study changes in receptor biology during liver regeneration and endotoxemia in rats.

The hepatic asialoglycoprotein receptor is responsible for rapid clearance of desiaylated glycoproteins from the circulation by receptor-mediated endocytosis. Previous in vitro studies in hepatocyte preparations from rats subjected to partial hepatectomy (PH) of 70% to stimulate hepatic regeneration showed decreased asialoglycoprotein (ASGP) receptor binding. We used an ASGP receptor-targeted hepatic magnetic resonance imaging (MRI) agent, BMS 180550, to demonstrate similar changes in receptor biology in vivo. BMS 180550 is an arabinogalactan-coated ultrasmall superparamagnetic iron oxide preparation. Arabinogalactan is a ligand for the ASGP receptor and, thereby, targets the contrast agent exclusively to hepatocytes. Hepatic uptake of BMS 180550 was assessed by sequential precontrast and post-contrast MRI in rats subjected to PH of 70%. In regenerating liver 1 and 3 days after PH, the maximum decrease in hepatic signal intensity (62.2% +/- 6.1 and 59.4% +/- 3.8, respectively) was significantly less than the maximum decrease seen in sham-operated animals at 1 and 3 days postsurgery (39.5% +/- 2.5 and 44% +/- 1.0, respectively). The time necessary to reach 80% of the maximum decrease in hepatic signal intensity, (t80), was less than 2 minutes in control rats and increased to 7.5 +/- 1.3 min and 11.0 +/- 2.3 minutes at 1 and 3 days post-PH, respectively. By 7 days post-PH, contrast-enhanced MRI no longer detected a difference in regenerating liver. Because BMS 180550 is taken up exclusively by the liver, clearance of the agent from the blood was used as a measure of hepatic clearance. Concentration-time curves constructed by measuring changes in blood T2 after an intravenous dose of BMS 180550 were used to determine clearance of the agent. Blood clearance of BMS 180550 in normal liver (15.4 +/- 1.08 mL/min) obeyed first-order kinetics and did not vary over the dose range tested (10 to 100 micromol/L/kg iron). One, 3, 7, and 14 days post-PH, clearance varied with dose, suggesting ASGP receptor saturation. As regeneration proceeded, the dose of contrast agent needed to cause a deviation from first-order kinetics increased, suggesting gradual recovery of ASGP receptor function. Hepatic relaxation was determined by in vitro spectroscopy 60 minutes after administration of graded doses of BMS 180550 and showed dose-dependent increases in relaxation. Kinetic analysis at 1 day post-PH demonstrated a decrease in the apparent k(m) and the maximum response, R(max), suggesting a decrease in the number of functional asialoglycoprotein receptors with concomitant increase in receptor affinity. Systemic endotoxemia, which normally accompanies hepatic regeneration induced by PH, also decreased clearance of BMS 180550 and slowed hepatic uptake of the contrast agent. Altered BMS 180550 pharmacokinetics in endotoxin-treated rats was enhanced by prior administration of small doses of competing ligand. Our studies document the value of BMS 180550 in following changes in ASGP function that accompany PH or systemic endotoxemia. This agent may be useful in assessing the degree of hepatic regeneration in patients with clinical liver disease.

Animals↗
PubMed2003

A possible role of cholesterol-sphingomyelin/phosphatidylcholine in nuclear matrix during rat liver regeneration.

BACKGROUND/AIMS: Phospholipids and cholesterol in chromatin have been previously demonstrated. The lipid fraction changes during cell proliferation in relation to activation of enzymes of phospholipid metabolism. The aim of the present work is to clarify if chromatin lipids may derive or not from nuclear matrix and if they have different roles. METHODS: The subnuclear fractions were isolated from rat hepatocyte nuclei and the lipid fraction was extracted and analysed by chromatography in normal and regenerating liver. The phosphatidylcholine-sphingomyelin metabolism enzymes activity was assayed, by using radioactive substrates. RESULTS: In nuclear matrix, cholesterol and sphingomyelin are respectively five and three times higher than those present in chromatin; the amount of phosphatidylcholine, which it is enriched in saturated fatty acids, is lower, thus indicating a less fluid structure. The lower content in phosphatidylcholine may be justified by the phosphatidylcholine-dependent phospholipase C activity, which increases during liver regeneration, reaching a peak at the beginning of S-phase, when also cholesterol and sphingomyelin increase. CONCLUSIONS: The nuclear matrix lipids are independent from chromatin lipids; the ratio cholesterol-sphingomyelin/phosphatidylcholine is higher and, as a consequence, nuclear matrix is less fluid in relation to DNA synthesis, suggesting a specific role of nuclear matrix as a structure involved in DNA duplication.

Animals↗
PubMed1988

Expression of the insulinoma gene rig during liver regeneration and in primary cultured hepatocytes.

We have isolated a novel gene, rig (rat insulinoma gene) from rat insulinomas. In the present study, rig was found to be expressed in rat regenerating liver and in primary cultured rat hepatocytes. The level of rig mRNA was increased at the proliferative phase of liver regeneration. In synchronously cultured hepatocytes, the rig mRNA level was elevated at the G1 phase of the cell cycle and the rig-protein was accumulated in the nuclei during the S phase. These results indicated that rig could be involved in a more general way in growth or cell replication.

Adenoma, Islet Cell↗
PubMedDate not supplied

[Comparative study of the ESR spectra of normal and regenerating liver tissue in mice].

Low temperature ESR spectra of gamma-irradiated samples of mouse liver regenerating after partial hepatectomy were studied. As compared to ESR spectra of gamma-irradiated samples of health animals liver, in regenerating liver samples new ESR signals from paramagnetic centres S(2.0005) and S(2.0025) were revealed; these signals were earlier recorded by the authors in gamma-irradiated samples of hepatoma 22a. It is concluded that the paramagnetic centres S(2.0005) and S(2.0025) are typical of proliferating tissues of different ethiology.

Animals↗
PubMed1984

[Liver regeneration and the immune system. 1. In vitro and in vivo activation of lymphocytes by liver regeneration].

When syngeneic lymphocytes and mitomycin C (MMC) treated regenerating liver cells prepared from a partial hepatectomized mice are cultured together, the in vitro DNA synthetic response is activated (sMLHLR: syngeneic mixed hepatectomized liver cell-lymphocyte culture). Ia+ Kupffer cells play an important role as stimulators in the responses, since the stimulating activity of regenerating liver cells is lost by the pretreatment of them with anti-Ia monoclonal antibody plus complement or the removing Kupffer cells from them. The lymphocytes are activated also in vivo during liver regeneration after a partial hepatectomy. Because, when lymphocytes prepared from hepatectomized mice are cultured with regenerating liver cells, lymphocytes are stimulated to accelerate their DNA synthesis in a typical manner of the secondary immune responses (secondary sMLHLR). In primary sMLHLR, the responder cells are mainly Lyt-1+ whereas in secondary sMLHLR they are mainly Lyt-2+. The mechanism of changing the Lyt phenotype of major responder cells from Lyt-1 to Lyt-2 during sMLHLR is discussed.

Animals↗
PubMed1992

Reorganization of the endocytic compartment in regenerating liver.

Antibodies raised to two membrane proteins present in rat liver endosomal fractions were used to study changes occurring in the endocytic compartment of hepatocytes during liver regeneration. Antibodies to the 42-kDa subunit (RHL-1) of the asialoglycoprotein receptor showed, by Western blotting of liver microsomes and endosomes, that there was a reduced expression of the receptor in liver 24 h following a partial hepatectomy. Immunocytochemical staining of thin sections of regenerating livers using these antibodies indicated that there was an intracellular relocation of endocytic structures in hepatocytes. The two main endocytic regions immunocytochemically stained in normal liver--one located beneath the sinusoidal plasma membrane and the other abutting the bile canaliculus--were replaced, in regenerating liver, by staining more closely associated with a region underlying the baso-lateral plasma membrane. A 140-kDa pI 4.3 calmodulin-binding protein located in endocytic and plasma membranes was also demonstrated, using a radio-iodinated calmodulin-binding assay, to be present at reduced levels in endosomes isolated from regenerating livers. Antibodies to this calmodulin-binding protein stained the hepatocyte's cytoplasm in a punctate manner. However, in regenerating liver, the staining was located in regions underlying the baso-lateral and apical plasma membrane of hepatocytes. Together, the results demonstrate that a reorganization of the endocytic compartment has occurred in hepatocytes 24 h following hepatectomy, with two endosomal proteins becoming relocated to a region below the baso-lateral-apical surface regions of hepatocytes.

Animals↗
PubMed1991

The immediate-early growth response in regenerating liver and insulin-stimulated H-35 cells: comparison with serum-stimulated 3T3 cells and identification of 41 novel immediate-early genes.

Liver regeneration provides a unique system for analysis of mitogenesis in intact, fully developed animals. Cellular immediate-early genes likely play an important role in cell cycle regulation and have been extensively studied in mitogen-stimulated fibroblasts lymphocytes but not in liver. We have begun to characterize the immediate-early growth response genes of mitogen-stimulated liver cells, specifically, regenerating liver and insulin-stimulated Reuber H-35 hepatoma cells, and to address differences in growth response between different cell types. Through subtraction and differential screening of cDNA libraries from regenerating liver and insulin-treated H-35 cells, we have extensively characterized 341 differentially expressed clones and identified 52 immediate-early genes. These genes have been partially sequenced and subjected to Northern (RNA) blot analysis, and 41 appear to be novel. Surprisingly, two-thirds of these genes are also expressed in BALB/c 3T3 cells, but only 10 were identified in previous studies of 3T3 cells, and of these, 6 include well-known genes like jun and fos, and only 4 are novel. Approximately one-third of the immediate-early genes identified in mitogen-stimulated liver cells or serum-stimulated NIH 3T3 cells are expressed in a tissue-specific fashion, indicating that cell type-specific regulation of the proliferative response occurs during the immediate-early period. Our findings indicate that the immediate-early response is unusually complex for the first step in a regulatory cascade, suggesting that multiple pathways must be activated. The abundance of immediate-early genes and the highly varied pattern of their expression in different cell types suggest that the tissue specificity of the proliferative response arises from the particular set of these genes expressed in a given tissue.

Animals↗
PubMed1997

Effects of short and long term ethanol on the activation of signal transducer and activator transcription factor 3 in normal and regenerating liver.

Interleukin-6 (IL-6) induced activation of Signal Transducer and Activator Transcription Factor 3 (Stat3) is a critical step in liver regeneration. Chronic ethanol consumption is known to increase the plasma concentration of IL-6, yet the ability of the liver to regenerate and the regenerative induction of several IL-6 initiated events are impaired in chronic alcoholic liver disease. We hypothesized that chronic ethanol consumption inhibits IL-6 dependent signal transduction. To test this hypothesis, the effect of ethanol on the Stat3 signal transduction pathway was studied in the adult rat liver. In vitro treatment of freshly isolated normal adult rat hepatocytes with 50-100 mM ethanol for 30 min blocked IL-6-induced Stat3 activation. Long-term ethanol intake in vivo significantly attenuated the activation of Stat3 induced either in vivo by partial hepatectomy or in vitro by IL-6. In contrast, short-term ethanol consumption enhanced the regenerative induction of Stat3 but inhibited IL-6 induced Stat3 activation. These data suggest that the inhibition of liver regeneration by chronic ethanol consumption is, at least in part, mediated by modulating the activation of Stat3.

Administration, Oral↗
PubMed2006

Liver regeneration.

During liver regeneration after partial hepatectomy, normally quiescent hepatocytes undergo one or two rounds of replication to restore the liver mass by a process of compensatory hyperplasia. A large number of genes are involved in liver regeneration, but the essential circuitry required for the process may be categorized into three networks: cytokine, growth factor and metabolic. There is much redundancy within each network, and intricate interactions exist between them. Thus, loss of function from a single gene rarely leads to complete blockage of liver regeneration. The innate immune system plays an important role in the initiation of liver regeneration after partial hepatectomy, and new cytokines and receptors that participate in initiation mechanisms have been identified. Hepatocytes primed by these agents readily respond to growth factors and enter the cell cycle. Presumably, the increased metabolic demands placed on hepatocytes of the regenerating liver are linked to the machinery needed for hepatocyte replication, and may function as a sensor that calibrates the regenerative response according to body demands. In contrast to the regenerative process after partial hepatectomy, which is driven by the replication of existing hepatocytes, liver repopulation after acute liver failure depends on the differentiation of progenitor cells. Such cells are also present in chronic liver diseases, but their contribution to the production of hepatocytes in those conditions is unknown. Most of the new knowledge about the molecular and cellular mechanisms of liver regeneration is both conceptually important and directly relevant to clinical problems.

Animals↗
PubMed1996

Liver regeneration 3: Regulation of signal transduction during liver regeneration.

The liver has a tremendous capacity to regenerate. For example, after extensive hepatic resection, remaining hepatocytes proliferate to restore the mass of the organ within days to weeks. This proliferative response is fascinating because hepatocytes rarely replicate in the healthy adult liver. Instead, these cells perform highly specialized functions and exemplify mature, terminally differentiated cells. Therefore it is somewhat surprising that the liver can repopulate while performing its many obligate, organ-specific functions. Study of the regenerating liver remnant after partial hepatectomy has helped to delineate mechanisms that regulate proliferation and liver-specific functions in individual hepatocytes, as well as those that coordinate the behaviors of different liver cell populations to balance organ growth and tissue-specific gene expression. Hence, this review will focus on inter- and intracellular signals that regulate the hepatocyte phenotype after PH.

Animals↗
PubMedDate not supplied

Effect of long term insulin infusion into rat portal vein on regenerating liver.

The effect of long term intraportal infusion of insulin on liver regeneration has been studied in rats 24, 36 and 48 hrs after partial hepatectomy. Our studies showed an enhancement by insulin of some parameters of rat liver regeneration, i.e. a rapid increase of the DNA and RNA levels as well as the TTK activity in the whole liver homogenate and all the subcellular fractions examined. The influence of insulin was marked during the whole time of experiment, but the most significant changes occur during the first 24 hrs after partial hepatectomy.

Animals↗
PubMed1995

NOR-2 (neuron-derived orphan receptor), a brain zinc finger protein, is highly induced during liver regeneration.

Zinc-finger proteins are involved in several cellular processes. Some of these proteins are implicated in the primary cellular response in regenerating liver and mitogen-stimulated cells. Using a rat cDNA brain library, we have isolated a clone designated NOR-2, encoding a protein containing two zinc-finger motifs and whose expression is highly induced during G0/G1 transition. We analysed the expression of NOR-2 mRNAs during early growth in regenerating liver and in both insulin-stimulated H4-II cells and pheochromocytoma-derived cell line PC12 treated by NGF. In these systems, there is an early, rapid and transient accumulation of NOR-2 mRNAs. The induction of NOR-2 mRNAs does not require de novo protein synthesis, since it is not prevented by cycloheximide treatment. Mobility shift assays show that NOR-2 protein binds to NBRE, a target sequence for r-NGFI-B family. Structurally, NOR-2 is closely related to the recently identified NOR-1 factor. Therefore, like NOR-1, NOR-2 belongs to the r-NGFI-B sub-family of nuclear receptors superfamily.

Amino Acid Sequence↗