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PubMed1994

Changes in cell cycle-associated gene expression in a model of impaired liver regeneration.

Following partial hepatectomy (PH) there is compensatory regeneration of the remnant liver which eventually restores hepatic mass and function. The response to PH was studied in normal BALB/c and athymic nude mice, a model of impaired liver regeneration. Following PH, nude mice demonstrated diminished peak hepatic [3H]thymidine uptake and delayed liver mass restoration through 60 h post-PH. However, between 72-120 h there was no significant difference in mass restoration between the groups. The expression of genes associated with different stages of the cell cycle was evaluated in both models. In nude mice, there was an increase in peak expression of c-jun transcripts, while c-myc transcript expression was moderately attenuated. Thymidine kinase (TK) and cyclin-dependent kinase 1 (CDK1) mRNA expression was also diminished in athymic nude mice. The results suggest that while the defect in the regenerative response of the nude mouse after PH affects events in several phases of the cell cycle, mass restoration of the liver is only delayed and not attenuated.

Animals↗
PubMed1987

Liver regeneration during immunosuppression.

As a preface to studies on the feasibility of liver segment transplantation, we studied the course of liver regeneration in immunosuppressed rats. Partial hepatectomies were performed in young adult male rats who were then treated with daily cyclosporine, dexamethasone, the combination of both agents, or vehicle. Body weight, liver weight, and liver DNA content were measured in subgroups of rats studied at various times after partial hepatectomy. All treated animals experienced weight loss, a phenomenon most marked in animals treated with both dexamethasone and cyclosporine. The DNA content of regenerating liver increased initially after partial hepatectomy in all animals. Restoring their original hepatic DNA in a fashion indistinguishable from controls, animals treated with cyclosporine increased liver DNA four fold within the first six days after partial hepatectomy. Animals treated with dexamethasone and both dexamethasone and cyclosporine increased their complement of liver DNA 2.5 fold, to 80% of that originally present. After day 6, the combined cyclosporine and dexamethasone treatment group became extremely catabolic and experienced a sharp decline in liver DNA. We conclude that despite the deleterious effects of cyclosporine and dexamethasone, especially in combination, on weight gain following partial hepatectomy, these agents do not prevent DNA synthesis and the accretion of new liver mass. We are encouraged by these studies to proceed with experimental studies on the normal growth and repair of liver segments transplanted into an immunosuppressed host.

Animals↗
PubMed1998

Transforming growth factor alpha levels in liver and blood correlate better than hepatocyte growth factor with hepatocyte proliferation during liver regeneration.

Transforming growth factor alpha (TGFalpha) and hepatocyte growth factor (HGF) are mitogens for hepatocytes in vitro and in vivo, produced by hepatocytes or nonparenchymal cells such as stellate cells in the liver. It is still uncertain whether TGFalpha and HGF are essential for liver regeneration. To assess the role of these growth factors in liver regeneration, their circulating and hepatic levels were studied in various rat models of liver regeneration. Hepatic and plasma HGF levels were increased with increased number of mitotic hepatocytes in rats after partial hepatectomy or carbon tetrachloride intoxication. However, hepatic HGF levels were decreased despite an increased number of mitotic hepatocytes and increased or unchanged plasma HGF levels in rats given phenobarbital and in rats after dimethylnitrosamine intoxication, which can induce hepatic necrosis after apoptosis of hepatic stellate cells. In contrast, hepatic and serum TGFalpha levels were increased in all of the models. In sham-operated rats with no increased number of mitotic hepatocytes, hepatic and circulating levels of HGF were increased, whereas those levels of TGFalpha were unchanged. The results indicate that TGFalpha levels in liver and blood more closely correlate with hepatocyte mitogenesis than HGF levels.

Animals↗
PubMed2000

Kupffer cell depletion by CI2MDP-liposomes alters hepatic cytokine expression and delays liver regeneration after partial hepatectomy.

BACKGROUND: Although Kupffer cells (KCs) are capable of producing important growth-stimulating cytokines, their role in liver regeneration following partial hepatectomy (PH) remains poorly understood. METHODS: In the present study liver regeneration was studied after KC-depletion by intravenous administration of liposome-encapsulated dichloromethylene-diphosphonate (C12MDP), a method known to physically eliminate KCs. Furthermore, splenectomy was performed one week prior to PH to exclude the effect of C12MDP-liposomes on macrophage populations in the spleen. RESULTS: KC-depletion was confirmed in cryostat liver sections stained with the monoclonal antibody ED2, a marker for resident tissue macrophages. Forty-eight hours after PH, the cumulative hepatocyte DNA synthesis, as determined in liver sections by the hepatocyte bromodeoxyuridine labeling index, was significantly decreased in KC-depleted rats when compared to control-rats. The weight of the remnant liver, expressed as a percentage of the initial liver weight, was significantly less at 96 h after PH in KC-depleted rats. KC-depletion abolished the hepatic interleukin-6 (IL-6) and interleukin-10 (IL-10) mRNA synthesis and decreased hepatic expression of tumor necrosis factor-alpha (TNF-alpha), hepatocyte growth factor (HGF) and transforming growth factor-beta1(TGF-beta1) mRNA after PH, as was assessed by reverse-transcriptase polymerase chain reaction (RT-PCR). Moreover, at 4 h after PH the systemic release of IL-6 was significantly decreased in KC-depleted rats. CONCLUSION: We conclude that KCs are important for hepatocyte regeneration after PH. Delayed liver regeneration in KC-depleted rats can be explained, at least in part, by an imbalanced hepatic cytokine expression, thereby suppressing important growth-stimulating cytokines.

Animals↗
PubMed1996

Analysis of the structure and expression of the augmenter of liver regeneration (ALR) gene.

BACKGROUND: The gene encoding the hepatotrophic factor Augmenter of Liver Regeneration (ALR) has recently been cloned in the rat. The availability of the mouse form of ALR would allow the analysis of the role of this factor in the physiology of liver and other organs, while the identification of the human homolog would allow the transfer of the great wealth of information that has been generated in animal models to clinically oriented pilot trials, and eventually the therapeutic application of this information. MATERIALS AND METHODS: Standard molecular biology approaches have been used to determine the genomic structure of the ALR gene in the mouse, and to characterize the ALR transcript and its protein product. The human ALR cDNA was also isolated and the amino acid sequence of the human gene product deduced. The mapping of mouse and human ALR genes on mouse and human chromosomes was then completed. RESULTS: The protein coding portion of the mouse ALR gene is comprised of three exons, the first containing the 5' untranslated sequence and the initial 18 bases after the ATG translation initiation codon, the second exon encompasses 198 bases, and the third exon contains the remaining portion of the protein coding sequence. Rat, mouse, and human ALR genes (and protein products) were found to be highly conserved and preferentially expressed in the testis and in the liver. The ALR gene maps to the mouse chromosome 17, in a region syntenic with human chromosome 16, where the T/t region has also been mapped. CONCLUSIONS: ALR appears to be a protein with important physiologic properties, not exclusively limited to liver regeneration, with roles that are involved in the synthesis or stability of the nuclear and mitochondrial transcripts that are present in actively regenerating cells, particularly the germ cells of the testes.

Amino Acid Sequence↗
PubMed1985

Effect of branched chain amino acids on liver regeneration after partial hepatectomy.

The authors investigated the effect of the enrichment of commercial amino acid solutions with branched chain amino acids on the development of liver regeneration. Partial (65-70%) hepatectomy was performed on male Wistar rats (140-160 g body weight). Starting with the day of the operation, amino acid solutions normally used in clinical practice and the same solutions enriched with branched chain amino acids were administered by stomach tube; 24, 48 and 96 h after the operation the animals were decapitated. The onset of DNA synthesis was found to be more rapid in animals given the enriched solutions. Once regeneration had started, the stimulant effect of an increased supply of branched chain amino acid on liver regeneration was smaller. Nevertheless, even in the later phase after partial hepatectomy branched chain amino acids had a stronger stimulant effect on liver regeneration after partial hepatectomy than an energy supply in the form of sorbitol.

Amino Acids, Branched-Chain↗
PubMed1999

Modulation of the gene network connected to interferon-gamma in liver regeneration from oval cells.

Suppression subtractive hybridization was used to clone genes associated with proliferation of oval cells in rat liver regenerating after a 70% partial hepatectomy combined with the feeding of 2-acetylaminofluorene. A subset of the identified genes comprised interferon-gamma receptor alpha subunit (IFN-gammaRalpha), gp91phox, interleukin-1beta (IL-1beta), lymphocyte function-associated molecule-1alpha (LFA-1), eukaryotic initiation factor-2-associated 67-kd protein (eIF-2-associated 67-kd protein), and alpha-fetoprotein, which constitute part of the cellular program modulated by IFN-gamma. Therefore, expression analysis performed by Northern blotting and immunohistochemistry were extended to include IFN-gamma, the IFN-gamma receptor beta subunit (IFN-gammaRbeta), three secondary response genes induced by interaction of IFN-gamma with IFN-gamma receptor complexes, ie, IL-1beta-converting enzyme (ICE), intercellular adhesion molecule-1 (ICAM-1), and urokinase-type plasminogen activator receptor (uPAR), and a cytokine inducing IFN-gamma expression, ie, interleukin-18 (IL-18). The Northern blot analysis showed that all examined genes were modulated when progenitor-like oval cells were activated and recruited for liver regeneration. Immunohistochemistry localized the subunits of the IFN-gamma receptor complex, IFN-gammaRalpha and IFN-gammaRbeta, the secondary response genes uPAR and ICAM-1, the IFN-gamma-inducing factor IL-18, and ICE to the ductular structures of oval cells. In contrast, during liver regeneration after a 70% partial hepatectomy, only modulation of IL-1beta and ICE was observed. Our results, therefore, indicate that IFN-gamma-mediated events may be particularly important when cells in the bile ductules must respond to liver damage by production of ductular oval cells.

2-Acetylaminofluorene↗
PubMed1990

Transforming growth factor receptors in liver regeneration following partial hepatectomy in the rat.

Transforming growth factors alpha and beta (TGF-alpha and TGF-beta) are produced in the liver and appear to play an important role in the regulation of hepatic growth. We investigated changes in receptors for these polypeptide growth factors in regenerating liver after partial hepatectomy in the rat with comparisons to livers from normal and sham-operated animals. In normal rats, binding of 125I-epidermal growth factor (EGF) to liver membranes was fully and competitively displaced by TGF-alpha, indicating that these two growth factors share similar sites on the same hepatic receptor. Scatchard analyses revealed that EGF receptors bound EGF with 4- to 8-fold higher affinity than TGF-alpha. Following partial hepatectomy or sham operation, EGF/TGF-alpha receptor number decreased by 25, 40, and 55% at 12, 24, and 72 h, respectively. In all cases. Scatchard analysis obtained with EGF yielded a linear plot indicating a single population of binding sites with a dissociation constant (Kd) of approximately 0.9 nM. Scatchard analysis of TGF-beta binding showed that liver membranes from sham-operated and normal rats express binding sites with a Kd of approximately 35 pM. In contrast, membranes obtained from 12-, 24-, and 72-h regenerating livers were altered in a manner consistent with uncovering or appearance of a higher affinity site. Affinity labeling of liver plasma membranes with 125I-TGF-beta revealed two predominant proteins with Mr 85,000 and 66,000. In unfractionated membrane preparations, two other proteins with Mr 105,000 and approximately 150,000 were seen. Following partial hepatectomy the major change in affinity-labeled proteins was a small (10-25%) but consistent decrease in the Mr 85,000 species. These results show that receptors for TGF-alpha and TGF-beta are modulated after partial hepatectomy, a further indication that these polypeptides may have an important role in liver regeneration.

Animals↗
PubMed2005

Relationship between expression of cyclin D1 and impaired liver regeneration observed in fibrotic or cirrhotic rats.

BACKGROUND AND AIM: The mechanisms responsible for impaired regenerative ability after hepatic resection observed in chronic liver disease are not fully understood. We have examined the relationships between an altered expression of cell cycle-related proteins in regenerating liver after partial hepatectomy and the impaired regenerative process observed in fibrotic and cirrhotic rats. METHODS: We performed 70% partial hepatectomy in both control and porcine serum-induced fibrotic rats, and 45% partial hepatectomy in thioacetamide-induced cirrhotic rats because of the high mortality associated with 70% partial hepatectomy. Liver regeneration was monitored by proliferating cell nuclear antigen labeling index and the expression of G1 regulatory cell cycle-related proteins was determined by immunoblot analysis. RESULTS: Compared with controls, hepatocyte DNA synthesis, and induction of cyclin D1 and p21(CIP1) proteins were delayed but not suppressed in porcine serum-induced fibrotic rats and markedly inhibited in thioacetamide-induced cirrhotic rats. p27(KIP1) protein levels were unaffected by partial hepatectomy and did not differ among all three groups. CONCLUSION: Two distinct rat models of liver fibrosis and cirrhosis showed markedly different proliferative responses after partial hepatectomy. The delay or failure of cyclin D1 induction, but not the increase of p21(CIP1) or p27(KIP1) might be responsible for their impaired liver regeneration.

Animals↗
PubMedDate not supplied

Effect of acute ethanol consumption on hepatic lysosomal enzymes and calcium concentration during rat liver regeneration.

Effect of alcohol consumption on the activity of two lysosomal nucleases, deoxyribonuclease II (DNAase II) and ribonuclease II (RNAase II) and calcium concentration have been studied during liver regeneration of Sprague-Dawley rats over a period of 10 days following 70% partial hepatectomy. Liver weight was completely restored in partially hepatectomized rats at 8 days in both sexes, but ethanol treatment resulted in only a partial restoration of liver weight at 10 days. Specific activity of DNAase II in partial hepatectomized animals increased by 50-75% at 6-12 hrs above sham operated controls, and the specific activity of RNAase II increased 2.3 fold at 6 hr, while calcium concentration decreased by 50% at 6-12 hrs. Ethanol treatment masked and/or delayed the increase in the specific activity of both enzymes at early stages of liver regeneration and also masked the decrease in calcium concentration. These results indicate that ethanol consumption delays the process of liver regeneration by altering the activity of lysosomal nucleases and calcium concentration.

Alcohol Drinking↗
PubMed2003

HIP/PAP stimulates liver regeneration after partial hepatectomy and combines mitogenic and anti-apoptotic functions through the PKA signaling pathway.

The HIP/PAP (=human Reg-2) C-type lectin encoding gene is activated in primary liver cancers. In normal liver, the protein is undetectable in normal mature hepatocytes and found only in some ductular cells, representing potential hepatic progenitor cells. The aim of this study was to examine the consequences of human HIP/PAP expression in the liver of transgenic mice. We demonstrated that HIP/PAP stimulated liver regeneration after partial hepatectomy. To further investigate the enhanced liver regeneration observed in vivo, primary cultures of hepatocytes were used to evaluate the mitogenic and anti-apoptotic properties of HIP/PAP. HIP/PAP increased hepatocyte DNA synthesis and protected hepatocytes against TNF-alpha plus actinomycin-D-induced apoptosis. HIP/PAP anti-apoptotic effects against TNF-alpha were clearly demonstrated when protein kinase A activity was specifically inhibited by KT5720, and HIP/PAP stimulated PKA-dependent phosphorylation of the proapoptotic Bad protein at Ser-112, suggesting that HIP/PAP may compete with cAMP to stimulate PKA activity. Overall, our results led us to propose a new role for a C-type lectin, HIP/PAP, as a hepatic cytokine that combines mitogenic and anti-apoptotic functions regarding hepatocytes, and consequently acts as a growth factor in vivo to enhance liver regeneration.

Animals↗
PubMed1985

Ranitidine as an inhibitor of liver regeneration.

The effects of ranitidine, a new H2-receptor antagonist, on liver regeneration were investigated using a protocol described previously. The animals in Group I had standard two-thirds hepatectomy. In Group II, the rats received an 8 mg/kg intramuscular dose of ranitidine immediately and 24 and 48 hours after two-thirds hepatectomy. In Group III, the rats had the same amounts of ranitidine after a sham operation. Mortality rate, liver weight restoration, mitotic activities of the residual livers, and serum levels of aminotransferases were examined from 24 hours to 14 days after operation. The mortality was very high in Group II (45 percent), whereas no rats died in Group I, and only 1 of 35 animals died in Group III. Administration of ranitidine after hepatectomy resulted in suppression not only of liver restoration, but also of the mitotic activities of hepatocytes. The serum aminotransferase levels in Group II had a tendency to increase after hepatectomy, compared with the levels in Group I. Using light microscopy, we detected that the hepatectomized group treated with ranitidine (Group II) underwent profound liver steatosis and marked dilatation of sinusoidal spaces. The present and previous observations by us indicate that ranitidine also inhibits, like cimetidine, liver regeneration after hepatectomy. The causes of the inhibitory effects of both cimetidine and ranitidine on hepatocyte cell division have also been discussed herein.

Animals↗
PubMedDate not supplied

Possible endocrine control by follistatin 315 during liver regeneration based on changes in the activin receptor after a partial hepatectomy in rats.

BACKGROUND/AIMS: Activin A is an autocrine inhibitor of cell growth in the liver. The biological activity of activin A is mediated by a heteromeric receptor complex. Follistatin (FS) binds to activin and inhibits its biological effects, and acts as a negative regulator of muscle cells. The role of activin receptors during liver regeneration following a hepatectomy has not been fully assessed. This study investigates the mechanism underlying how activin receptors regulate hepatocyte growth, and the effects of intravenous administration of FS during liver regeneration. METHODOLOGY: The expression of both activins and activin receptors in the liver after a 70% partial hepatectomy (HT) was assessed by RT-PCR and immunohistochemistry. FS 315 or 288 was infused for different periods of time based on changes in hepatocyte activin receptor expression after HT. RESULTS: Activin receptor expression peaked between 48 and 72 hours after HT. 72 hours after HT, an injection of FS 315 resulted in a more potent stimulation of DNA synthesis and produced a greater increase in body weight compared with the control rats. CONCLUSIONS: The expression of activin receptors after peak DNA synthesis might be a key component in the downregulation of DNA synthesis. Intravenous administration of FS 315 might promote liver regeneration and have anabolic actions.

Activin Receptors, Type II↗
PubMed1992

Liver regeneration in recipients and donors after transplantation.

Reduced-size liver grafts from related donors may not be of an optimal size for adequate function in the recipient. Therefore, liver-graft regeneration is clinically important. We evaluated liver regeneration by liver-volume determinations with serial computed tomography scans in four recipients (aged 9 months to 12 years) and their donors (all fathers of the recipients) after living-related liver transplantation. Standard liver volume was calculated from the recipient's body-surface area. In each recipient, the size of the transplanted liver tended to converge to the standard liver volume with time, regardless of whether initial liver-graft volume was smaller or larger than standard liver volume. In addition, transplanted liver in the recipient regenerated much faster than remnant liver in the donor, even though both consisted of the same hepatocytes, which suggests that regeneration is regulated mainly by factors other than the hepatocytes themselves.

Adult↗
PubMed1989

Characterization by morphometric model of liver regeneration in the rat.

A new stereological approach to the study of liver regeneration in the rat is described. The method employs a morphometric model consisting of number and size, as well as surface and volume fractions of hepatocytes, their nuclei, cytoplasm, and their relation to the sinusoidal bed. With this technique, it was found that 8 hr after partial hepatectomy, the number of nuclei increased as did the nucleus/cytoplasm ratio, suggesting an early hyperplastic phase. These data, which have not been reported in other studies, underline the importance of evaluating the complex phenomenon of liver regeneration using a stereological approach, which is more representative of all morphometric changes occurring inside and outside the hepatocyte.

Animals↗