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PubMed2002

Increased hepatic Forkhead Box M1B (FoxM1B) levels in old-aged mice stimulated liver regeneration through diminished p27Kip1 protein levels and increased Cdc25B expression.

Recent liver regeneration studies indicate that maintaining hepatic Forkhead Box M1B (FoxM1B) expression in 12-month-old (old-aged) Transthyretin-FoxM1B transgenic mice increases hepatocyte proliferation and expression of cell cycle regulatory genes. Because these transgenic CD-1 mice maintain FoxM1B levels during the aging process, we conducted the current study to determine whether adenovirus delivery of the FoxM1B gene (AdFoxM1B) is sufficient to stimulate liver regeneration in old-aged Balb/c mice. Here we show that AdFoxM1B infection of old-aged mice caused a significant increase in FoxM1B expression, hepatocyte DNA replication, and mitosis following partial hepatectomy. This stimulation in hepatocyte S-phase progression was associated with diminished protein expression and perinuclear localization of cyclin-dependent kinase (Cdk) inhibitor p27(Kip1) (p27) protein following partial hepatectomy. In contrast, old-aged mice infected with control virus displayed high hepatocyte levels of p27 protein, which had been localized to the nucleus prior to S-phase. Furthermore, we found that restoring FoxM1B expression did not influence p27 mRNA levels, and this new finding implicates FoxM1B in regulation of p27 protein levels. Likewise, AdFoxM1B-infected regenerating livers displayed elevated S-phase levels of Cdk2 kinase activity compared with old-aged mice infected with control virus. Furthermore, restoring FoxM1B expression in old-aged mice caused elevated levels of Cyclin B1, Cyclin B2, Cdc25B, Cdk1, and p55CDC mRNA as well as stimulating Cdc25B nuclear localization during liver regeneration, all of which are required for mitosis. These studies indicated that an acute delivery of the FoxM1B gene in old-aged mice is sufficient to re-establish proliferation of regenerating hepatocytes, suggesting that FoxM1B can be used for therapeutic intervention to alleviate the reduction in cellular proliferation observed in the elderly.

Adenoviridae↗
PubMed1998

Transcription of the rat p53 gene is induced by a 39kDa protein binding to the p53 promoter region during the liver regeneration.

The adult rat liver is normally in a state of growth arrest. However, cell loss such as partial hepatectomy can induce the proliferation of the hepatocytes. Early after partial hepatectomy, the concentration of p53 mRNA increases during the prereplicative phase. In this study, we identified the cis-regulatory element involved in the induced transcription of the rat p53 gene by DNase I footprinting assay. This element had a partial homology to the AP1 recognition motif, but the competition study with AP1 oligonucleotide showed that this element was not the AP1 recognition motif. The molecular weight of the binding protein to this motif was determined as 39 kDa by southwestern blotting analysis. In vitro transcription assay with the competitor containing the binding motif showed that the 39 kDa protein binding to the element was required for the induced transcription of the rat p53 gene during the liver regeneration.

Animals↗
PubMed2002

Increased intraabdominal pressure impairs liver regeneration after partial hepatectomy in rats.

BACKGROUND: There are many experimental studies showing that increased intraabdominal pressure (IAP) reduces liver blood flow, leading to ischemia and portal venous congestion. But, there is no study evaluating the effect of increased IAP on liver regeneration. It is well known that acute liver ischemia and portal venous congestion impair liver regeneration. We, therefore, aimed to determine the effect of increased IAP on liver regeneration in this study. METHODS: Sprague-Dawley rats underwent partial hepatectomy with or without IAP of 12-14 mm Hg for 24 h or sham operation. Rats were randomly divided into six groups: two sham-operated groups, two hepatectomy groups, and two hepatectomy with increased IAP groups. Mitotic index, proliferating cell nuclear antigen (PCNA)-labeling index, and liver regeneration rate as liver regeneration parameters were studied on day 1 or on day 4 after operation. Additionally, serum aspartate transaminase (AST) level and histopathological changes in intestinal mucosa were studied. RESULTS: Hepatectomy with/without increased IAP groups had significantly higher serum AST levels than the sham-operated group on day 1. Serum AST level was found to be significantly higher in the hepatectomy with increased IAP group than in the other groups on day 4. Intestinal mucosal injury was found in the hepatectomy with increased IAP groups on days 1 and 4. Mitotic index and PCNA-labeling index were markedly higher in all hepatectomy with/without increased IAP groups than in the sham-operated groups. However, together with liver regeneration rate, both indices were significantly less in the hepatectomy with increased IAP groups than in the hepatectomy groups both on day 1 and on day 4. CONCLUSION: Maintenance of IAP between 12 and 14 mm Hg for 24 h impaired liver regeneration after partial hepatectomy in rats.

Abdomen↗
PubMed1980

Immunolocalization of fetal aldolase isoenzymes in rat regenerating liver after carbon tetrachloride intoxication.

Light and electron microscopic immunolocalization of adult and fetal aldolase isoenzymes has been studied in rat liver 72 h after CCL4 intoxication. As in rat regenerating liver after partial hepatectomy, fetal aldolases A and C were located in sinusoidal cells (Kupffer and endothelial cells) whereas adult aldolase B was present in hepatocytes only. Our results are different from those obtained with fetal and cancerous livers; they suggest that control mechanisms of gene regulation different in liver regeneration and in cancer.

Animals↗
PubMed1993

Liver regeneration in trypsin-fed partially hepatectomized rats.

Young adult Sprague-Dawley rats were partially hepatectomized (two-thirds organ removal) and administered a basal diet supplemented with various animal- and plant-derived enzymes (trypsin, alpha-chymotrypsin, pepsin, lipase, alpha-amylase, malt diastase, ficin and bromelain) over a post-operative period of up to 10 days. Porcine or bovine dialyzed and lyophilized crystalline trypsin products containing 2400-3200 NF u/mg in addition to enteric-coated tablets with trypsin to chymotrypsin in a ratio of 6:1, were tested at supplementary levels of up to 4980 u/g ration. With the weight of tissue regenerated or the liver increment as indicator, trypsin in excess of 1000-1200 u/g ration proved inhibitory. This effect did not extend to alpha-chymotrypsin (levels of up to 4000 u/g diet) and the remaining 6 enzyme products specified above, nor to the s.c. injection of trypsin daily at 12,860 u/rat for the 1st 7 days. The last route promoted little change in increment with soy bean trypsin inhibitor (8.0 mg/rat daily for days 1 to 9). When a portion of the group fed a trypsin supplement of 2000 u/g was injected with phenobarbital i.p. at 80 mg/kg daily on each of the last 3 days, the resulting liver increment rose to the control range. As with lysine and arginine, acids of pertinence in tryptic proteolysis, no significant change was elicited by feeding a diet supplemented with peptone from tryptic digestion of casein. The enzyme-containing diets fed to sham-operated rats over a similar interval, did not affect the wet- or dry-liver weight per 100 g body weight. Microsomal parameters as total protein, cytochrome P-450 and the enzymes, aminopyrine demethylase and benzo[a]pyrene hydroxylase of livers from the partially hepatectomized or sham-operated rats fed trypsin and the other enzyme diets, presented no significant changes in the respective levels. The possible action of dietary trypsin in conjunction with inhibitors and growth factors controlling liver regeneration is discussed.

Animals↗
PubMed2003

Mitochondrial glutathione content determines the rate of liver regeneration after partial hepatectomy in eu- and hypothyroid rats.

BACKGROUND/AIMS: Mitochondrial glutathione has been postulated to affect mitochondrial function and liver regeneration. METHODS: Mitochondrial respiration, total and oxidized glutathione, and liver regeneration were assessed after partial hepatectomy in glutathione-depleted and in hypothyroid rats with/without supplementation of glutathione ester. RESULTS: Mitochondrial, cytosolic and circulating glutathione levels were lower in glutathione-depleted rats. Hepatectomy was followed by significant changes of intra- and extracellular glutathione and of mitochondrial respiration. In glutathione-deficient rats, the recovery of mitochondrial function and the liver regeneration were delayed. Administration of glutathione ester partially corrected the fall of cytosolic and mitochondrial glutathione following hepatectomy, reduced mitochondrial oxidative damage, and accelerated the restoration of mitochondrial respiration and the rate of liver regeneration. In hypothyroid rats, intracellular glutathione homeostasis and mitochondrial respiration were impaired already at baseline; slower regeneration and mitochondrial oxidative alterations were observed after hepatectomy. Glutathione ester ameliorated the regenerative response in hypothyroid rats by providing higher concentrations of cytosolic and mitochondrial glutathione. CONCLUSIONS: Glutathione depletion and hypothyroidism affect the mitochondrial function during liver regeneration. Liver regenerates more slowly in glutathione-depleted and in hypothyroid rats. The earlier restoration of mitochondrial function and the higher rate of proliferation in glutathione ester treated rats suggest that the maintenance of intracellular glutathione facilitates liver regeneration.

Animals↗
PubMed1996

Liver regeneration and hepatocarcinogenesis in transforming growth factor-alpha-targeted mice.

Transforming growth factor-alpha (TGF alpha), a member of the epidermal growth factor receptor ligand family, has been implicated in the regeneration and transformation of liver. Our recent development of mice that are homozygous for a disrupted TGF alpha gene allowed us to assess the requirement for this growth factor in these complex processes. We report here that although a 70% hepatectomy produced a significant increase in hepatic TGF alpha protein levels in wild-type mice, liver regeneration nevertheless proceeded normally in the absence of the growth factor. The hepatocyte labeling indices determined for homozygous targeted and wild-type mice at 36 and 48 h after hepatectomy were comparable, and the total liver DNA to body weight ratios 8 d after hepatectomy were essentially identical for the two genotypes. These results indicate that TGF alpha, is not necessary for liver regeneration. To test its requirement in liver carcinogenesis, young mice were administered single doses of diethylnitrosamine (DEN) with or without subsequent chronic treatment with the promoting agent phenobarbital (PB). Both wild-type and homozygous mutant male mice treated with DEN or DEN plus PB developed multiple preneoplastic foci or tumors by 9 mo of age with relatively high incidence. However, while five of 88 tumors in wild-type mice attained a diameter greater than 5 mm and were classified as hepatocellular carcinomas, none of 132 tumors in livers of targeted mice reached this size. Furthermore, three of these large wild-type tumors expressed significantly elevated levels of TGF alpha protein compared with normal liver. These results indicate that TGF alpha is not required for early events in chemically induced hepatocarcinogenesis but suggest that it could be important in the progression from small preneoplastic foci to large tumors.

Animals↗
PubMed1991

[Effects of single ethanol administration on liver regeneration in rats].

The effects of a single ethanol administration on liver weight gain, RNA synthesis, DNA synthesis, and polyamine metabolism as parameters of liver regeneration in rat liver after partial hepatectomy were studied. Ethanol, given 1 hr before partial hepatectomy at the dose of 3 g/kg, inhibited RNA synthesis 4 hr after partial hepatectomy and DNA synthesis 24 hr after partial hepatectomy in the liver, but did not affect liver weight gain. Further, we studied the effects of a single ethanol administration on polyamine metabolism in order to elucidate the mechanism of the inhibition of liver regeneration by ethanol. Ethanol inhibited the increase in the putrescine level in the liver 4 and 8 hr after surgery, which was a metabolic product of ornithine decarboxylase. But spermidine and spermidine levels in the liver were not affected by ethanol administration. Hepatic spermidine N1-acetyl transferase activity increased by ethanol administration 6 hr after partial hepatectomy in compensation for the suppression of putrescine. Judging from these results, a single dose of ethanol inhibited liver regeneration polyamine metabolism after partial hepatectomy in rats.

Acetyltransferases↗
PubMed1999

Role of shear stress and immune responses in liver regeneration after a partial hepatectomy.

This report reviews studies addressing the new concepts in liver regeneration after a partial hepatectomy (PHx). The review begins with an overview of the immunologic mechanisms of liver regeneration after PHx, especially regarding Kupffer cells and extrathymic T cells of the regenerative liver in the cell-mediated immunity, based on major histocompatibility complex I and II antigens. Attention is then devoted to "on and off" studies in liver regeneration after PHx, by hypothesizing the shear stress based on the fact that the portal flow against hepatocytes or sinusoidal endothelial cells triggers their regeneration after a partial hepatectomy and controls the volume of the regenerating liver by the stimulating the cell surface modulator (CSM) of hepatocytes and sinusoidal endothelial cells (SEC). We propose that the acute elevation of shear stress after PHx influences the adhesion between SEC and intrahepatic leukocytes. These concepts are expected to positively contribute to the future research on liver regeneration after PHx.

Animals↗
PubMed2002

The presence and the role of chromatin cholesterol in rat liver regeneration.

BACKGROUND/AIMS: It has been shown that cholesterol is necessary in early G1 phase during cell duplication. In the present research we have studied the presence of cholesterol in the hepatocyte chromatin lipid fraction and its behaviour in liver regeneration. METHODS: Hepatocyte nuclei and chromatin were isolated from normal and regenerating rat liver. The lipid fraction was extracted and analysed by chromatography. The activity of sphingomyelin-synthase in the chromatin was evaluated using labelled phosphatidylcholine. RESULTS: In the chromatin, the amount of cholesterol is similar to that of sphingomyelin, and it increases in chromatin digested with exogenous sphingomyelinase or proteinase K. It may be concluded that a complex, formed by cholesterol, sphingomyelin and proteins, is present in the chromatin. The particular affinity between sphingomyelin and cholesterol in chromatin with respect the nuclear membrane may be tentatively explained as due to the enrichment in saturated fatty-acids of the chromatin sphingomyelin. Moreover the cholesterol inhibits the chromatin sphingomyelin-synthase activity. During liver regeneration, an increase in chromatin cholesterol is observed between 6 and 18 h after hepatectomy, when the neutral-sphingomyelinase activity increases and the sphingomyelin-synthase is inhibited. CONCLUSIONS: The cholesterol is present in the chromatin and its amount changes in relation to cell proliferation in regenerating liver.

Animals↗
PubMed1994

Expression and activation of cdks (1 and 2) and cyclins in the cell cycle progression during liver regeneration.

In normal adult liver, hepatocytes are arrested in G0, and they rapidly respond to a mass loss by a definite number of divisions. Thus, taking advantage of the in vivo regenerative capacity of the liver following partial hepatectomy, we have analyzed both expression and activation of p34cdc2 (= cdk1) and p33cdk2 through the cell cycle, particularly during the long lasting G1 phase and in the G1/S transition. While p33cdk2 is constantly expressed during the cell cycle, p34cdc2 is completely absent in resting hepatocytes and remains unexpressed for up to 20 h after partial hepatectomy, a time period corresponding to the G1 phase and G1/S transition, and then accumulates in the S, G2, and M phases. No histone H1 kinase activity is detected during the G1 phase, while two peaks of p34cdc2 kinase activity are observed during the S and M phases and only one peak of p33cdk2 kinase activity in the S phase. p34cdc2 forms complexes with both cyclins A and B while p33cdk2 is associated with cyclin A only. Surprisingly, cyclins E and D1 are present in resting liver and with modest variation throughout the cell cycle. Taken together, our data provide evidence that the pattern of G1-associated proteins in hepatocytes during liver regeneration is distinct from that described in other cell types.

Animals↗
PubMed1976

A connection between the production of prostaglandins during liver regeneration and the DNA synthetic response.

The concentration of PGE equivalents in rat liver in vivo was increased during liver regeneration. The probability that this increase reflected a stimulation of prostaglandin synthesis was confirmed in vitro by the ability of homogenates of regenerating liver tissue to synthesize PGE2 and PGF2alpha from arachidonate. Indomethacin prevented these prostaglandin changes, and the subsequent increase in DNA synthesis. The administration of indomethacin to rats was found to induce a hypocalcemia, and to block the hypercalcemic action of parathyroid hormone. It is suggested that the influence of prostaglandins on DNA synthesis involves calcium metabolism.

Animals↗
PubMed2001

Expression of suppressors of cytokine signaling during liver regeneration.

The cytokines TNF and IL-6 play a critical role early in liver regeneration following partial hepatectomy (PH). Since IL-6 activates signal transducers and activators of transcription (STATs), we examined whether the suppressors of cytokine signaling (SOCS) may be involved in terminating IL-6 signaling. We show here that SOCS-3 mRNA is induced 40-fold 2 hours after surgery. SOCS-2 and CIS mRNA are only weakly induced, and SOCS-1 is not detectable. SOCS-3 induction after PH is transient and correlates with a decrease in STAT-3 DNA binding and a loss of tyrosine 705 phosphorylation. This response is markedly reduced in IL-6 knockout (KO) mice. TNF injection induces SOCS-3 mRNA in wild-type mice (albeit weakly compared with the increase observed after PH) but not in TNF receptor 1 or IL-6 KO mice. In contrast, IL-6 injection induces SOCS-3 in these animals, demonstrating a requirement for IL-6 in SOCS-3 induction. IL-6 injection into wild-type mice also induces SOCS-1, -2, and CIS mRNA, in addition to SOCS-3. Together, these results suggest that SOCS-3 may be a key component in downregulating STAT-3 signaling after PH and that SOCS-3 mRNA levels in the regenerating liver are regulated by IL-6.

Animals↗
PubMed2006

Hepatocyte 'priming' and increase in transforming growth factor-beta1 mRNA expression are delayed in hypothyroid versus euthyroid rats during liver regeneration.

Hypothyroidism decreases liver weight and delays the compensatory liver growth after partial hepatectomy (PH) as compared with the euthyroid condition. The aim of this study was to investigate, in hypothyroid rats, the mRNA expression of genes modulating these effects, focusing on c-fos and c-myc, hallmarks of hepatocyte 'priming', and on transforming growth factor-beta1 (TGF-beta1) and its receptor, the transforming growth factor-beta1 receptor-type II (TbetaR-II), negative regulators of liver growth. Euthyroid and hypothyroid male Wistar rats underwent 70% PH and total RNA was isolated from frozen liver samples removed at basal state and during regeneration, 0-144 h after surgery. In this study, we show for the first time that, in the basal liver state, hypothyroidism increased TGF-beta1 and TbetaR-II mRNA levels by 45% and 30%, respectively, as compared with the euthyroid condition and, after PH, resulted in a approximately 12-h delay in the activation of c-fos and c-myc mRNA expression. Moreover, the increase in TGF-beta1 mRNA levels, detected 24-48 h after PH in euthyroid rats, was delayed by 72 h in hypothyroid rats, occurring when a concomitant reduction in TbetaR-II was measured. These results suggest that, in hypothyroid rats, at the basal liver level, the increase in mRNA expression of genes that negatively regulate liver growth might be involved in the decrease in liver weight and that, after PH, the delay of hepatocyte 'priming' and coordinated changes in mRNA expression of negative regulators of liver regeneration might be involved in delaying the regenerative process.

Animals↗
PubMed1991

[Consideration on the mechanism of liver regeneration on experimental results].

Liver has enough functional capacity and regeneration ability. Liver parenchymal cells are usually stable, and it is thought being at stage of Go in cell cycle. But liver cells are easily into progressive stage and the liver recovers its functions and volume after partial hepatectomy or liver injury. Usually the studies of liver regeneration are done by studying control of growth of isolated hepatocytes in primary culture in vitro, and by pathological considerations of experimental injured models of liver in vivo. In this paper, we considered known several hepatotrophic factors including our experimental results, and regeneration mechanisms by noticing appearance of albumin positive hepatocytes in injured Nagase analbuminemic rat (NAR).

Aging↗