Phosphatases of rat liver. II. Adenosinetriphosphate dephosphorylation in regenerating liver.
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Adenosine Triphosphate↗
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[Comparative studies on liver-regenerating properties of certain liver-protective drugs].
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Liver↗
Differential regulation and expression of jun, c-fos and c-myc proto-oncogenes during mouse liver regeneration and after inhibition of protein synthesis.
In order to obtain information in vivo about the possible relationships between early response gene products, we have analysed the expression of c-myc, c-fos and jun proto-oncogenes in regenerating mouse liver. We show that c-myc, c-fos, jun B, c-jun and jun D mRNA expression is transiently increased soon after partial hepatectomy, jun and fos expression being induced earlier (30 min) than that of c-myc (1-2 h). C-fos, jun B and c-jun mRNA expression is dramatically enhanced (50 fold) while that of jun D and c-myc is weaker (less than 10 fold), but lasts longer. Moreover, the relative contributions of transcriptional and post-transcriptional regulations are unique for each proto-oncogene analysed. These results suggest that following the growth signal delivered by partial hepatectomy, the five proto-oncogenes analysed are all involved in the progression of hepatocytes through G1; however, due to their differential regulation and kinetics, they might play different roles in the changes in gene expression that occur during the transition from quiescence to proliferation. When protein synthesis is inhibited by injection of cycloheximide, the expression of c-myc, c-fos, jun B, c-jun and jun D mRNA is also transiently increased. Although this increase is mainly due to post-transcriptional mechanisms, c-myc, c-jun, jun D and, to a lesser extent, jun B transcription is enhanced, suggesting that labile repressor-like molecules may inhibit transcription of these genes in the quiescent liver. Moreover, the kinetics of c-myc, c-fos and jun mRNA induction are not identical, showing that different components are involved in their turnover or stability.
Animals↗
Pre-replicative association of multiple replicative enzyme activities with the nuclear matrix during rat liver regeneration.
As a step toward the molecular elucidation of the putative replicational apparatus associated with the nuclear matrix, we have investigated the possible matrix association of several replicational related enzymes. In addition to the previously identified DNA polymerase alpha, DNA primase, 3'-5' exonuclease, RNase H, and DNA methylase were all recovered at significant levels (20-30% of total nuclear activity) in nuclear matrix isolated from regenerating rat liver during maximal in vivo replication (22 h post-hepatectomy). In contrast, DNA ligase was not detected on the nuclear matrix even though significant activity was present in isolated nuclei. Examination of the replicative dependency of these enzyme activities following partial hepatectomy revealed pre-replicative elevations which were distinct for each matrix-bound enzyme. A second late-replicative peak in DNA methylase is consistent with a role of this matrix-bound enzyme in the maintenance of the inheritable methylation pattern. Mild sonication resulted in a significant release of all of these activities except RNase H. A major portion of the matrix-solubilized DNA polymerase alpha, DNA primase, 3'-5' exonuclease, and DNA methylase activities cosedimented on sucrose gradients between approximately 8-12 S. Our results are consistent with the organization of at least a portion of these replicative enzymes into nuclear matrix-bound replicational complexes. We also propose a novel pre-replicative assembly model of the matrix-bound replicational apparatus in which DNA primase plays an initial and critical role.
Animals↗
[Critical time function of the influence of liver regeneration on carcinogenesis in rat liver].
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Animals↗
[Features of nuclear genome transcription at early steps of liver regeneration: expression of DNA fractions with different repeating sequence frequencies].
The mode of hybridization of dRNA fraction from normal and regenerating rat liver with purified fractions of repeating and unique sequences of DNA was studied. In order to repress the reassociation of DNA the nucleic acids were annealed in a solution of 2 x SSC--80% formamide at 48 degrees. The differential hybridization curves suggest that the amount of transcripts with a high DNA sequence frequency increases, while the complexity of transcripts of unique DNA sequences decreases 3 hrs after partial hepatectomy. Simultaneously the amount of RNA transcribed from the unique and moderately repeating DNA fractions remains practically unchanged.
Animals↗
[Liver regeneration: morphological aspects of the liver during the first 4 days following partial hepatectomy].
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Animals↗
Partial hepatectomy and laparoscopic-guided liver biopsy in rhesus macaques (Macaca mulatta): novel approach for study of liver regeneration.
BACKGROUND AND PURPOSE: Although valuable information has been gained using a rodent partial hepatectomy model to assess liver regeneration, the ability to apply this research to humans remains uncertain. Thus, liver regeneration was assessed in a non-human primate, the rhesus macaque (Macaca mulatta). METHODS: One animal underwent 60% hepatectomy, a second animal underwent 30% hepatectomy, and control surgery (cholecystectomy) was performed on two separate animals. Laparoscopic-guided liver biopsy was performed on days 1, 2, 7, 14, and 30 after surgery. Changes in hemoglobin concentration and alanine transaminase activity were assessed, and liver regeneration was evaluated by measuring the expression of Ki-67. RESULTS: All animals survived surgery and laparoscopy. Substantial liver regeneration was induced in the animal that underwent 60% hepatectomy. Excellent tissue specimens were obtained via laparoscopic-assisted liver biopsy. CONCLUSIONS: Sixty percent partial hepatectomy in rhesus macaques appears to be an excellent model for the study of hepatocellular regeneration. The procedure was safe, and effectively induced liver regeneration. In addition, laparoscopic-guided liver biopsy allows observation of changes in the liver remnant as regeneration develops, and provides excellent tissue specimens for analysis. Thus, this rhesus macaque partial hepatectomy model will allow further characterization of liver regeneration in a species closer to humans.
Animals↗
Change in caspase-3-like protease in the liver and plasma during rat liver regeneration following partial hepatectomy.
Recent studies have shown that many factors orchestrate liver regeneration after a two-thirds partial hepatectomy (PH). However, the termination mechanism in liver regeneration has not been thoroughly studied. In this paper, we report that the activity of liver caspase-3-like protease, which is specifically activated in apoptosis, increases 18, 36, and 48 hr after PH during maximal hepatocyte proliferative activity. This is the first study that shows the activation of an apoptosis-executing enzyme during physiological liver regeneration. These results suggest that apoptosis is induced in each surge of DNA synthesis as the termination mechanism. When phenoxybenzamine, an alpha-blocker that has been reported to inhibit DNA synthesis during liver regeneration, was injected 8 hr after PH, the caspase-3-like activity in the liver peaked at 15 hr after PH and the enzyme activity also increased in plasma at 18 and 24 hr after PH in sharp contrast to the case of normal regeneration. These results indicate that extensive apoptosis is caused by phenoxybenzamine and that the secondary necrosis of apoptotic cells results in the increase of caspase-3-like protease activity in the plasma.
Animals↗
Met provides essential signals for liver regeneration.
Genetic analysis in mice has demonstrated a crucial role of the Met tyrosine kinase receptor and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), in development of the liver, muscle, and placenta. Here, we use conditional mutagenesis in mice to analyze the function of Met during liver regeneration, using the Mx-cre transgene to introduce the mutation in the adult. After partial hepatectomy in mice carrying the Mx-cre-induced Met mutation, regeneration of the liver is impaired. Comparison of signal transduction pathways in control and mutant livers indicates that Met and other signaling receptors cooperate to fully activate particular signaling molecules, for instance, the protein kinase Akt. However, activation of the Erk1/2 kinase during liver regeneration depends exclusively on Met. Signaling crosstalk is thus an important aspect of the regulation of liver regeneration. Analysis of cell cycle progression of hepatocytes in conditional Met mutant mice indicates a defective exit from quiescence and diminished entry into S phase. Impaired liver regeneration is accompanied by compensatory physiological responses that include prolonged up-regulation of HGF/SF and IL-6 in peripheral blood. Our data demonstrate that the HGF/SF/Met signaling system is essential not only during liver development but also for the regeneration of the organ in the adult.
Animals↗
Liver regeneration in rats after complete and partial occlusion of the portal blood influx.
The role of portal blood influx in liver regeneration was studied in rats. Partial hepatectomy with removal of 45% of the liver mass was performed after end-to-side portacaval shunt (PCS) leading to complete diversion of portal blood from the liver, or after side-to-side PCS causing partial portal blood deprivation. Liver resection was limited to 45% to avoid the high mortality rate in rats with vascular anastomoses and 70% hepatectomy, but it did not change the pattern of liver regeneration. The total RNA and DNA content, the rate of DNA synthesis and the number of hepatocyte mitoses in regenerating liver were measured in comparison to sham-operated controls. Complete occlusion of the portal blood influx did not block hepatoproliferative response, but caused a significant decrease and delay of regeneration. Partial preservation of portal flow in rats with side-to-side PCS markedly improved liver regeneration in comparison to end-to-side PCS, but the process was slower than in the control group.
Animals↗
Gene expression during the priming phase of liver regeneration after partial hepatectomy in mice.
Understanding the gene-expression patterns during liver regeneration may help to reveal how regenerative processes are initiated and controlled as well as shed new light onto processes that lead to liver disease. Using high-density oligonucleotide arrays, we have examined the gene-expression program in the livers of mice after partial hepatectomy. A time course was constructed for gene expression between 0 and 4 h after partial hepatectomy, corresponding to the priming phase of liver regeneration. The genomic program for liver regeneration involves transcription-factor generation, stress and inflammatory responses, cytoskeletal and extracellular matrix modification, and regulation of cell-cycle entry. The genome-wide changes that are observed provide a detailed and comprehensive map of the initial priming stage of liver regeneration.
Animals↗
Intact signaling by transforming growth factor beta is not required for termination of liver regeneration in mice.
Transforming growth factor beta (TGF-beta) is a potent inhibitor of hepatocyte proliferation in vitro and is suggested to be a key negative regulator of liver growth. To directly address the role of TGF-beta signaling in liver regeneration in vivo, the TGF-beta type II receptor gene (Tgfbr2) was selectively deleted in hepatocytes by crossing "floxed" Tgfbr2 conditional knockout mice with transgenic mice expressing Cre under control of the albumin promoter. Hepatocytes isolated from liver-specific Tgfbr2 knockout (R2LivKO) mice were refractory to the growth inhibitory effects of TGF-beta1. The peak of DNA synthesis after 70% partial hepatectomy occurred earlier (36 vs. 48 hours) and was 1.7-fold higher in R2LivKO mice compared with controls. Accelerated S-phase entry by proliferating R2LivKO hepatocytes coincided with the hyperphosphorylation of Rb protein and the early upregulation of cyclin D1 and cyclin E. However, by 120 hours after partial hepatectomy, hepatocyte proliferation was back to baseline in both control and R2LivKO liver. Regenerating R2LivKO liver showed evidence of increased signaling by activin A and persistent activity of the Smad pathway. Blockage of activin A signaling by the specific inhibitor follistatin resulted in increased hepatocyte proliferation at 120 hours, particularly in R2LivKO livers. In conclusion, TGF-beta regulates G(1) to S phase transition of hepatocytes, but intact signaling by TGF-beta is not required for termination of liver regeneration. Increased signaling by activin A may compensate to regulate liver regeneration when signaling through the TGF-beta pathway is abolished, and may be a principal factor in the termination of liver regeneration.
Activins↗
Intracellular trafficking during liver regeneration. Alterations in late endocytic and transcytotic pathways.
BACKGROUND/AIMS: Liver growth, induced by partial hepatectomy of the organ is a precisely regulated process during which a radical reorganisation of metabolism occurs as the hepatocytes become committed to enter the cell cycle. Recent studies have shown the importance of the endocytic compartment in the control of lipid and protein intracellular trafficking but also in the control of the signal transduction events, which eventually will trigger the initiation of DNA synthesis and the subsequent cell division. METHODS: We isolated endosomes at different times after partial hepatectomy in male rats and compared with endosomes isolated from sham-operated animals. Also, bile was collected and analysed by 2D-gel electrophoresis. RESULTS: The amount of late endosomes isolated from regenerating livers decreased, concomitant with decreased cathepsin D specific enzyme activity. Furthermore, secretion of horseradish peroxidase, pIgA and transferrin increased in the pre-replicative phase of liver regeneration. CONCLUSIONS: At the early stages of liver regeneration, the hepatocellular transport pathway towards degradation (late endosomes and lysosomal pathway) decreases, but the transcytosis and the bile secretion of several major proteins increases.
Animals↗
[Changes in the ploidies of hepatocyte nuclei of animals with transplantable tumors during liver regeneration and x-irradiation].
Alterations in ploidy of hepatocyte nuclei were followed in experiments on 190 rats with transplantable tumors during liver regeneration and x-ray irradiation. The presence of the growing transplantable tumor in the animal's body led to alterations in the nuclear structure of hepatocytes, manifesting in the increased ploidy. X-Ray irradiation brought about a rise in hepatocyte ploidy which was more remarkable the higher the dose. Under such conditions, polyploidy of hepatocyte nuclei was more pronounced in tumor-bearing rats than in those without tumors. An abrupt increase in ploidy of hepatocyte nuclei occurred in the regenerating liver of tumor-bearing animals both non-irradiated and, particularly, irradiated ones.
Animals↗
Expression of bcl-2 gene family during resection induced liver regeneration: comparison between hepatectomized and sham groups.
AIM: During liver regeneration cellular proliferation and apoptosis result in tissue remodeling to restore normal hepatic mass and structure. Main regulators of the apoptotic machinery are the Bcl-2 family proteins but their roles are not well defined throughout the liver regeneration. We aimed to analyze the expression levels of bcl-2 gene family members during resection induced liver regeneration. METHODS: We performed semi-quantitative RT-PCR to examine the expression level of bak, bax, bcl-2 and bcl-xL in 70% hepatectomized rat livers during the whole regeneration process and compared to that of the sham and normal groups. RESULTS: The expression of bak and bax was decreased whereas that of bcl-2 and bcl-xL was increased in hepatectomized animals compared to normal liver at most time points. We also reported for the first time that sham group of animals had statistically significant higher expression of bak and bax than hepatectomized animals. In addition, the area under the curve (AUC) values of these genes was larger in sham groups than the hepatectomized groups. CONCLUSION: The expression changes of bak, bax, bcl-2 and bcl-xL genes are altered not only due to regeneration, but also due to effects of surgical operations.
Animals↗
Does steatohepatitis impair liver regeneration? A study in a dietary model of non-alcoholic steatohepatitis in rats.
BACKGROUND: Impaired liver regeneration is a feature of alcoholic hepatitis, but the relative importance of alcohol, nutritional imbalance and inflammatory mediators in causing this effect is unclear. Non-alcoholic steatohepatitis (NASH) is a form of liver disease with similar morphology to alcoholic hepatitis, but the effect of this disorder on liver regeneration is unclear. We, therefore, examined the status of liver regeneration in a rat nutritional model of hepatic steatosis with inflammation, which is morphologically identical to NASH in humans. METHODS: Male Wistar rats received a methionine-choline-deficient diet (MCDD) for 4 weeks before experiments and both isocaloric pair-fed and ad libitum-fed rats were used as controls. Following partial hepatectomy (68%), the extent of hepatic regeneration was determined 24 h later using [3H]-thymidine incorporation and restitution of liver mass. RESULTS: There was no significant difference of [3H]-thymidine incorporation in MCDD-fed, pair-fed and ad libitum-fed rats (80+/-27, 78+/-11 and 80+/-6.3 d.p.m./microg DNA, respectively). Similarly, restituted liver masses in three groups of rats were not significantly different (17+/-3.8, 18+/-1.8 and 17+/-3.1% initial liver weight, respectively). CONCLUSIONS: The similarities in hepatic histology and cytochrome P450 2E1 induction between this nutritional model of hepatic steatohepatitis and alcoholic steatohepatitis imply that these two disorders share pathogenetic mechanisms. However, liver regeneration is not altered by NASH in rats, indicating that the nutritional and inflammatory changes that appear similar to those of alcoholic liver disease do not cause impairment of liver regeneration.
Animal Feed↗
Using higher-order crossings to distinguish liver regeneration indices in hepatectomized diabetic and non-diabetic rats.
BACKGROUND AND AIMS: Diabetes mellitus is implicated in several liver diseases; hence, its potential affection to liver regenerative capacity is an open research question. So far, only sporadic studies have addressed this issue, mainly using basic statistical techniques. The current study evaluated the ability of a novel technique, namely higher-order crossings (HOC), based on liver DNA biosynthesis and thymidine kinase (TK) enzymatic activity data, to discriminate liver regeneration processes between hepatectomized diabetic and non-diabetic rats. METHODS: We used 251 adult male rats, divided in two groups; diabetic by Alloxan injection and non-diabetic control, subjected to 70% partial hepatectomy and killed at different time intervals post-partial hepatectomy (PH) (0-240 h). The rate of tritiated thymidine (3HTdR) incorporation into hepatic DNA and the enzymatic activity of liver TK were estimated and, after proper interpolation, were analyzed using HOC sequences. Changes of the latter were captured and used as a means for linear discrimination between the two groups. RESULTS: Ninth-order HOC estimated for post-PH (24, 28, 40, 44, 72 and 84 h) exhibited linear discrimination for the rate of 3HTdR incorporation, whereas second-order HOC estimated for (44-72 h) post-PH exhibited linear discrimination for the TK enzymatic activity data. Fuzzy logic-based c-means cluster analysis of HOC provided distinct areas of group categorization (100% accuracy) for diagnostic distinctions (P < 0.001). The data grouping pointed out by the HOC-based analysis revealed an onset delay in the liver regeneration process when Alloxan diabetes was present (P < 0.05). CONCLUSIONS: Our results suggest that HOC have the potential to linearly discriminate between experimentally induced diabetic and non-diabetic liver regeneration post-PH processes, based on two liver regeneration indices, capturing the delay seen in the liver regeneration process due to Alloxan diabetes, fostering their use as an efficient classification tool. In this way, HOC could be used as an advanced, easily implemented and user-friendly method to thoroughly analyze liver regeneration processes.
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