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PubMed1973

Thymidine kinase and deoxyribonucleic acid metabolism in growing and regenerating livers from rats on controlled feeding schedules.

Rats accustomed to eating during the first 8h of a daily 12h dark period re-established about 80% of intact liver weight, protein and DNA within 4 days following partial hepatectomy; further increases were not observed. Liver thymidine kinase activity and thymidine incorporation into liver DNA exhibited marked daily oscillations during liver regeneration. Maximum values were observed near the end of the dark period both in intact growing rats and in rats partially hepatectomized 2h before the end of the dark period. The time of day of surgery affected thymidine kinase activity and thymidine incorporation into DNA at specific times following partial hepatectomy. This seriously affects the interpretation of reports of experiments where the time of day of killing has been held constant and time of surgery varied. Highly significant correlation coefficients were observed for thymidine incorporation before killing versus thymidine kinase activity at time of killing and for thymidine versus orotic acid incorporation into DNA of livers from rats partially hepatectomized 2h before the end of the dark period and killed at 12h intervals. Thymidylate phosphatase activity returned to the normal amount at a rate similar to that for liver protein. Thymidylate phosphatase did not affect the validity of the thymidine kinase assay. The relationship of [(14)C]orotic acid to [(3)H]thymidine incorporation into liver DNA varied with the time of day, with the age of the rat and during the regeneration of the liver.

Age Factors↗
PubMed2001

Effect of methylprednisolone on the kinetics of cytokines and liver function of regenerating liver in rats.

The participation of cytokines in the early stage mechanism of hepatocyte proliferation has already attracted attention. We investigated the effect of methylprednisolone (MDS), which inhibits the inflammatory response, given before and after a 70% partial hepatectomy in rats on the kinetics of tumor necrosis factor-alpha and Interleukin-6, liver cell function and the rate of liver regeneration. Serum Interleukin-6 levels of the MDS groups were significantly lower than those of the control group. Serum alanine aminotransferase, aspartate aminotransferase and hyaluronic acid levels were also significantly decreased, however, the serum albumin level showed high values in the MDS groups. In the MDS groups, MIB-5 labeling indices, a novel antibody reactive with the equivalent Ki-67 protein, which detects immunohistochemically all active parts of the cell cycle in the rat liver, were more pronounced than in the control group at an earlier time. However, in regard to 5-bromo-2-deoxyuridine (BrdU), there were no significant differences among the three groups. There were no differences in residual liver weight/body weight between the three groups after 336 h. In our study, MDS administration before or after a 70% partial hepatectomy decreased serum Interleukin-6 levels, and inhibited hepatic dysfunction. Therefore, we considered that beneficial effects of physiological doses of MDS in the peri-operative period should be confirmed in humans.

Journal Article↗
PubMed2002

Lack of intestinal bile results in delayed liver regeneration of normal rat liver after hepatectomy accompanied by impaired cyclin E-associated kinase activity.

BACKGROUND: The importance of bile in liver regeneration after hepatectomy is unknown, although we have recently shown that preoperative internal biliary drainage is superior to external biliary drainage for liver regeneration in obstructive jaundiced rats. This study examined the hypothesis that the presence or absence of bile in the intestinal tract modulates cyclins and cyclin-dependent kinases after hepatectomy in rats. METHODS: In male Wistar rats, bile was drained externally (ED group) or into the duodenum (ID group) for 7 days before 70% hepatectomy. Relative liver weight, DNA synthesis rate, and proliferating cell nuclear antigen labeling index were determined at the time of hepatectomy (day 0) and on days 1, 3, and 7 after hepatectomy. Posthepatectomy expressions of cyclin D1 and E and of cyclin D1- and E-associated kinases were serially analyzed. Hepatic function tests were performed. RESULTS: No significant difference in liver function was found between the 2 groups at hepatectomy except for the lower albumin level in the ED group. The relative liver weight was lower in the ED group than in the ID group on day 3 after hepatectomy (ED, 2.58% +/- 0.06%; ID, 2.84% +/- 0.08%; P <.05). Both the DNA synthesis rate and proliferating cell nuclear antigen labeling index in the ED group (77 +/- 36 disintegrations per minute/microg DNA and 8.3% +/- 1.9%, respectively) were lower than those in the ID group (262 +/- 50 disintegrations per minute/microg DNA and 21.6% +/- 5.6%, respectively) on day 1 after hepatectomy (P <.05, respectively). Cyclin D1-associated kinase activity and cyclin D1 expression were not significantly different between the 2 groups. Cyclin E-associated kinase activity was lower in the ED group than in the ID group at 18 hours after hepatectomy (ED, 84% +/- 17%; ID, 146% +/- 28% of the value at 0 hour in the ID group; P <.05), although expressions of cyclin E and p27 binding to cyclin E were not significantly different between the 2 groups. CONCLUSIONS: These results suggest that the absence of bile in the intestine delays liver regeneration associated with cyclin E-associated kinase inactivation after hepatectomy.

Amylases↗
PubMed2004

Animal models of liver regeneration.

Owing to its powers of regeneration, the liver is capable of in vivo "tissue engineering" which enables complete restoration of liver architecture and re-establishment of the specific functions of the liver after various types of liver injury. Our current understanding of liver regeneration forms the basis of modern liver surgery and is now taken into consideration in the treatment of many liver diseases, in liver transplantation and hepatic tissue engineering. These advances have been achieved primarily by studies of liver regeneration in animal models after partial hepatectomy, attention being focused on the general mechanisms of cell proliferation. In recent years, however, toxin-induced models of liver regeneration have assumed growing importance, and by studying the interaction between cell damage and cell regeneration have made possible an investigation of liver regeneration of greater clinical relevance. However, the mechanisms of liver regeneration in patients with pre-existing chronic liver damage such as liver cirrhosis are still largely unexplored. This review examines and critically appraises the various approaches to the study of liver regeneration in animal models, including both surgical and pharmacological approaches.

Animals↗
PubMed1985

The circadian optimal time for hepatectomy in the study of liver regeneration.

Standardized (light from 0600 to 1800) C3HS mice, hepatectomized at different circadian stages, were killed at 1400 (the peak time of mitotic activity in intact mice). The higher values of mitotic index were those of mice operated at 1400, 48 hr before. The curve of mitotic activity of the regenerating liver of mice operated at 1400 and that of mice operated at 0200 (an opposite time in the circadian stage) are, both, grossly in phase with the curves of mitotic index in young and adult mice liver. The amplitude of the first peak of mitotic activity in mice operated at 0200 was dramatically lower than that of animals operated at 1400. The same applies to hepatocytes as well as to the sinusoid litoral population of cells. It is concluded that 1400 hr, as contrast to 0200 hr, is an optimal time for hepatectomy if one wants to obtain the highest mitotic index first peak during regeneration in a normal phase position (the position of the mitotic index peak in the liver of normal young and adult mice).

Animals↗
PubMed1999

Effects of acute ethanol exposure on polyamine and gamma-aminobutyric acid metabolism in the regenerating liver.

Recently, it has been suggested that ethanol-induced inhibition of liver regeneration results from decreases in hepatic putrescine levels and/or increases in hepatic gamma-aminobutyric acid (GABA)ergic activity. Because putrescine can be metabolized by diamine (DAO) and monoamine (MAO) oxidases to GABA, we documented the effects of acute ethanol exposure on hepatic MAO or DAO activity following partial hepatectomy (PHx) in rats. We also documented the effects of ethanol on GABA transaminase (GABA-T), the enzyme responsible for GABA metabolism in the liver, and tissue putrescine and GABA levels. Adult, male Sprague-Dawley rats (200-250 g) were treated with either ethanol (3 g/kg) or equal volumes of saline by gastric gavage 1 h prior to a 70% PHx or sham surgery. Rats were then sacrificed (n = 5-7/group) at various times (0-72 h) post-PHx. Enzymatic activity and putrescine/GABA levels were determined by standard isotopic techniques and high-performance liquid chromatography respectively. Hepatic DAO activities in ethanol-treated rats were transiently higher than in saline-treated controls (30% increases at 6 h, p < 0.05). Hepatic MAO and GABA-T activities in acute ethanol-treated rats were essentially identical to saline-treated controls. Although hepatic putrescine levels were similar in ethanol- and saline-treated rats, hepatic GABA levels were approximately three times higher in ethanol-treated rats at 12 and 24 h post-PHx (p < 0.0001). In conclusion, the results of this study indicate that acute ethanol exposure has a limited effect on the enzymatic conversion of putrescine to GABA following partial hepatectomy in the liver. The results also indicate that increased GABAergic inhibition rather than decreased putrescine stimulation is more likely to play a role in ethanol-induced inhibition of hepatic regeneration.

4-Aminobutyrate Transaminase↗
PubMed1978

Morphology of nuclear ribonucleoproteins in the early period of liver regeneration.

A cytochemical study on the nuclei of hepatocytes in the regenerating liver after partial hepatectomy by the method of Higgins and Anderson was carried out. The behaviour of the ribonucleoprotein components of the nucleus, using EDTA according to Bernhard, revealed altered proportions of the fibrillar and granular components of the nucleoli in the early phase of regeneration and morphologic changes in nuclear RNP, especially in perichromatin fibrils. At 6 h after hepatectomy, the reaction with perichromatin fibrils (FP) was intense, localized around fields of condensed chromatin, which suggests intense transcription of extranucleolar RNA. The behaviour of the remaining nuclear ribonucleoproteins was uncharacteristic.

Animals↗
PubMed2005

Effects of emodin and double blood supplies on liver regeneration of reduced size graft liver in rat model.

AIM: To study the influences of emodin and reconstruction of double blood supplies on liver regeneration of reduced size graft liver in rat model. METHODS: A total of 45 SD-SD rat reduced size liver transplantation models were randomly divided into three groups (A-C). The conventional reduced size liver transplantation was performed on rats in group A, while the hepatic artery blood supply was restored in groups B and C. The emodin (1.5 mg/kg/d) was given by intraperitoneal route in group C only. The recipients were killed on the seventh day after the operation. The proliferative cell nuclear antigen (PCNA), TBil and ALT of serum were detected, and the pathological changes of liver cell were observed. RESULTS: The numbers of the rats that survived in A, B, and C group on the seventh day after operation were 14, 13, 13, respectively. The levels of TBil (31.5+/-5.2 micromol/L, 23.2+/-3.1 micromol/L vs 38.6+/-6.8 micromol/L), and ALT (5 351+/-1 050 nKat, 1300+/-900 nKat vs 5779+/-1202 nKat) in serum in groups B and C were lower than those in group A (P<0.05), while the expression of PCNA in groups B or C was higher than that in group A (22.0+/-3.5%, 28.2+/-4.2% vs 18.6+/-3.2%, P<0.05). The deeper staining nuclei, double nuclei, multi-nuclei and much glycogen were observed in liver cells of groups B and C, especially in group C, while fewer were found in liver cells of group A. CONCLUSION: The reconstruction of arterial blood supply is very important for rat liver regeneration after reduced size liver transplantation. Emodin has the effect of promoting liver regeneration and improving liver function in rats after reduced size transplantation. The possible mechanism is improving proliferation of liver cell and protecting liver cells from injury.

Animals↗
PubMed1989

c-myc and c-fos gene regulation during mouse liver regeneration.

We have examined the expression of c-myc and c-fos proto-oncogenes in regenerating mouse liver, in order to analyse the relative contributions of transcriptional and post-transcriptional regulations in vivo. We show that c-myc and c-fos transcription is induced after partial hepatectomy, and involves common mechanisms. A strong block to transcriptional elongation exists in normal liver, within the first exon of c-myc gene. This block is only slightly relieved during liver regeneration, although transcriptional initiation is transiently increased (4-6 fold). In contrast, transcription initiation of c-fos is induced while the transcriptional block within the first exon of the gene is almost completely abolished. The steady-state levels of both transcripts increased to high levels (50-100 fold) within 2-6 h after partial hepatectomy, and were maintained for at least 40 h in the case of c-myc. We conclude that post-transcriptional control mechanisms are largely responsible for the dramatic induction of c-myc mRNA in regenerating liver, while c-fos mRNA accumulation is the result of both an increased initiation and a relief of a transcriptional block to elongation. Induction of both genes in vivo with cycloheximide argues in favor of negative trans-acting proteins which regulate initiation and elongation of transcription.

Animals↗
PubMed2005

Expression of augmenter of liver regeneration (ALR) in human liver cirrhosis and carcinoma.

AIMS: To determine the expression of a protein termed augmenter of liver regeneration (ALR), recently found to have a specific and beneficial effect on the process of liver regeneration in normal and diseased human liver. METHODS AND RESULTS: ALR expression in normal and cirrhotic human livers with various underlying diseases as well as in tissue samples of hepatocellular carcinoma (HCC) and cholangiocellular carcinoma (CCC) was analysed by immunohistochemistry and quantitative reverse transciptase-polymerase chain reaction (RT-PCR). Expression analysis of ALR in total liver protein extracts by Western blotting showed mainly dimeric ALR protein. Immunohistochemically, cytosolic and perinuclear immunosignals were found in hepatocytes and cholangiocytes in normal, cirrhotic or cancerous liver tissue and only weak signals in some endothelial cells in normal livers. Quantitative mRNA analysis revealed significantly increased ALR expression in cirrhosis compared with normal liver tissue. In HCC and CCC ALR mRNA expression was also significantly enhanced compared with normal liver tissue, but expression levels did not differ from the matching non-neoplastic tissue in the same patient. CONCLUSIONS: The findings suggest an important role for ALR in hepatocellular regeneration in liver cirrhosis as well as in hepatocarcinogenesis and therefore its potential value in the clinical diagnosis of hepatic cirrhosis and cancer.

Aged↗
PubMed2006

Gene expression analysis identifies novel genes participating in early murine liver development and adult liver regeneration.

Adult liver tissue regeneration may recapitulate molecular events of liver organogenesis. As gaps in our understanding of the fundamental processes that govern development and regeneration of the liver still exist, we studied gene expression in the developing liver at embryonic day 9.5 post coitum (E d9.5 p.c.). Microarray data from E d9.5 p.c. as well as previously published data from embryonic day 11.5 post coitum (E d11.5 p.c.) and embryonic day 13.5 post coitum (E d13.5 p.c.) were subjected to cluster analysis. This led to the identification of 130 genes which were characterized by continuous expression at all stages of liver development with peak expression of 44 genes at E d9.5 p.c. Five of these genes, previously not known to be associated with early liver development or with adult liver regeneration were selected for further analysis. The expression of the genes was studied by real-time polymerase chain reaction at 0, 2, 4, 6, 12, 24 and 48 hr after partial hepatectomy in the adult liver. Two of the genes, growth arrest protein 43 (GAP43) and paired-like homeodomain transcription factor 2 (Pitx2) were exclusively detected at 24 hr, whereas the genes Twist1, Midkine, and zinc finger protein of cerebellum 1 (Zic1) each showed a specific expression profile in the regenerating liver with peak expressions at 4, 24, and 6 hr, respectively. In summary, we were able to identify novel genes, that may act as regulators during liver formation as well as in the regeneration phase of adult liver. This information may contribute to the development of new targets for the treatment of liver diseases in the future.

Animals↗
PubMed2005

Impaired hepatocyte survival and liver regeneration in Atm-deficient mice.

Atm is a stress-induced DNA damage checkpoint protein kinase with multiple roles in cell-cycle progression. Recent evidence indicates that Atm also plays a role in stem cell maintenance and self-renewal. It is not known whether Atm has a role during tissue regeneration. Using liver regeneration as a model system, we examined the role of Atm in this process. Here, we show that the expression levels of Atm protein were gradually increased during liver regeneration and this was correlated with the onset of DNA replication. The induction of Stat3 and JNK signaling, which are essential processes in normal regeneration response, was attenuated during the early phases of liver regeneration in Atm-deficient mice. P53 was transiently phosphorylated at serine 23 during liver regeneration in an Atm-dependent manner. In addition, we found that cyclin A induction was delayed and p21 was over-expressed, both of these processes were correlated with reduced and delayed DNA replication in Atm(-/-) mice during liver regeneration. Finally, we show that increased apoptosis was observed in Atm(-/-) mice in response to partial hepatectomy, indicating that Atm is required for the survival of hepatocytes. Collectively, these data indicate that liver regeneration is impaired in Atm-deficient mice. Given that liver is the first line of defense against environmental toxins, the elucidation of the function of Atm and Atm-mediated signaling pathways in liver metabolism and in response to environmental toxins is of fundamental interest.

Animals↗
PubMed2000

Combined interleukin 6 and soluble interleukin 6 receptor accelerates murine liver regeneration.

BACKGROUND & AIMS: Liver regeneration after loss of hepatic tissue leads to hepatocyte and nonparenchymal cell proliferation and rapid restoration of liver parenchyma. Interleukin (IL)-6 is a key inducer of transcription factors involved in liver regeneration. Whenever IL-6 activates target cells, it binds to a specific IL-6 receptor (IL-6R). The IL-6/IL-6R complex then associates with the signal transducer gp130, leading to activation of intracellular signaling. METHODS: We have recently constructed the designer cytokine Hyper-IL-6 consisting of soluble IL-6R covalently linked to IL-6, which directly stimulates gp130 even in the absence of membrane-bound IL-6R. We compared the influence of IL-6 and Hyper-IL-6 on liver regeneration after partial hepatectomy in mice. RESULTS: The IL-6/soluble IL-6 fusion protein Hyper-IL-6, but not IL-6 alone, led to an earlier onset of hepatocellular proliferation resulting in an acceleration of liver weight restoration. Also, during liver regeneration, soluble IL-6R levels were increased. CONCLUSIONS: These results emphasize a central role for IL-6 and soluble IL-6R in liver regeneration and indicate a possible therapeutic potential for the designer cytokine Hyper-IL-6 in clinical situations associated with liver regeneration such as acute hepatic failure or resection of chronically damaged liver tissue.

Animals↗
PubMed1993

Activation, proliferation, and differentiation of progenitor cells into hepatocytes in the D-galactosamine model of liver regeneration.

Rat liver regeneration was studied from 24 hours to 8 days after a single intraperitoneal injection of D-galactosamine (GalN). Morphological changes in the liver were analyzed in parallel with sequential changes in expression of histone-3 mRNA (a marker of cell proliferation), fetal alpha-fetoprotein (AFP) mRNA and gamma-glutamyl transpeptidase (GGT) (markers of fetal hepatocytes), and albumin mRNA and glucose-6-phosphatase (G6Pase) (markers of adult hepatocytes). Proliferation of nonparenchymal epithelial cells (NPC), detected in situ by [3H]thymidine labeling or histone-3 mRNA expression, began after 24 hours primarily in the portal area around the bile ducts. After 2 days, histone-3 labelling intensity increased in rows and clusters of NPC which expanded from the portal zone and invaded into the parenchyma. On days 3 and 5, NPC expressing his-3 mRNA expanded further, forming pseudo-ducts and islet-like structures (NPC structures). Proliferating NPC were positive for GGT. Some GGT positive cells were also positive for the fetal form of AFP mRNA, which lagged behind GGT by 24 hours and peaked on day 5. On day 3, some cells with the appearance of NPC expressed albumin mRNA. Double label in situ hybridization for fetal AFP and albumin mRNAs and dual histochemistry for GGT and G6Pase showed simultaneous expression of these markers in NPC on day 5. Other cells expressing fetal AFP mRNA or GGT on day 5 had a morphological appearance between NPC and hepatocytes (transitional cells). Proliferation of hepatocytes began on day 2, reached maximum on day 5 and then declined. Proliferating hepatocytes did not express fetal AFP mRNA or GGT. These findings indicate that after GalN injury, the liver responds by activation of progenitor cells that proliferate and then differentiate into mature hepatocytes. Adult hepatocytes can also proliferate after GAlN injury, but these hepatocytes do not undergo dedifferentiation/redifferentiation during regeneration of the hepatic lobule.

Albumins↗
PubMed1996

Hepatic protein synthesis and serum aminoacid levels during liver regeneration in young and old malnourished rats.

The aim of the present study was to measure protein synthesis in regenerating liver and to evaluate the impact of malnutrition in young and old rats. Two groups of male Wistar rats were used: young rats (4 months old) and old rats (18 months old). The rats were allocated to malnutrition or ordinary food intake for 1 week. Half of each group was sham-operated and the other was partially hepatectomized 2 days before the end of diet manipulation. Hepatic protein synthesis was significantly increased in all hepatectomized groups compared with their respective sham group: young well-nourished hepatectomized rats, 44%; young malnourished hepatectomized rats, 55%; old well-nourished hepatectomized rats, 47%; and old malnourished hepatectomized rats only 21%. Hepatic DNA content was unchanged in all groups and liver RNA content was higher in young malnourished hepatectomized rats (21%, P < 0.05). Serum total amino acid concentration did not change in young well-nourished hepatectomized and young malnourished hepatectomized rats. This value did not show significant changes between old well-nourished hepatectomized and old well-nourished sham, but it increased 14% (P < 0.05) in old malnourished hepatectomized. It was concluded that (a) regeneration is not impaired by malnutrition in young rats and may even be better than in rats eating a normal diet, and (b) the deleterious effect of aging is revealed once old animals are exposed to malnutrition. It is manifested in the decreased rate in hepatic protein synthesis observed in old malnourished hepatectomized rats and in the augmentation of total serum amino acid concentration, where the hypercatabolism induced by hepatectomy is significantly greater.

Age Factors↗
PubMed1989

Changes in lipoprotein binding and uptake by hepatocytes during rat liver regeneration.

The binding and uptake of cholesterol enriched lipoproteins by isolated hepatocytes was decreased at 16 hours after partial hepatectomy, with a tendency to return to control values as the regeneration proceeds. The number of lipoprotein binding sites of total cellular membranes remained similar to control at 16 and 24 hours. The plasma lipoprotein pattern, determined by electrophoretic analysis, showed a lower per cent of very low density lipoproteins (VLDL) and a higher per cent of low density lipoproteins (LDL) at 16 and 24 hours post-partial hepatectomy. At these times, plasma lecithin: cholesterol acyltransferase (LCAT) activity was decreased. It is intriguing to suggest that the regenerating liver could regulate the blood lipoprotein pattern and the uptake of lipoproteins by modulating the surface expression of the receptors.

Animals↗