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PubMed2005

Mitochondrial branched chain aminotransferase gene expression in AS-30D hepatoma rat cells and during liver regeneration after partial hepatectomy in rat.

Branched chain aminotransferase (BCAT) is the first enzyme in the catabolism of branched chain amino acids (BCAA). Unlike other amino acid degrading enzymes present in liver, BCAT is only expressed in extrahepatic tissues, and is not regulated by dietary protein, glucagon or glucocorticoids. However, the mitochondrial (m) isoform of BCAT is highly expressed in the fetal liver and rapidly decays after birth. The purpose of the present work was to establish if liver cells under conditions of rapid cell proliferation such as in hepatoma AS30D cells or during liver regeneration after partial hepatectomy were associated with an increase in the activity and expression of BCATm. BCAT activity in mitochondria of AS30D cells was 18.6 mU/mg protein. Western, Northern blot, and immunohistochemical analysis revealed that AS30D hepatoma cells expressed only BCATm. The apparent Km of BCATm in isolated AS30D cells mitochondria for leucine, isoleucine and valine was 1.0+/-0.02, 1.3+/-0.1 and 2.1+/-0.1 mM, respectively. The regenerated liver showed BCAT activity from day 3 to day 6, and the maximal BCAT activity (7.0 mU/mg protein) was on day 5. By day 14 after partial hepatectomy BCAT activity and expression was almost undetectable. Interestingly, there was a relationship between BCAT activity and the Mr. of the immunoreactive band of BCATm. The presence of a 41 kDa band was associated with BCAT activity, whereas the 43 kDa band with undetectable activity. The results of this study indicate that BCATm activity is required in liver cells under conditions of rapid cell proliferation.

Amino Acids, Branched-Chain↗
PubMedDate not supplied

The effect of trimetazidine on liver regeneration after partial hepatectomy under hepatic blood inflow occlusion.

BACKGROUND/AIMS: It has been shown that hepatic blood inflow occlusion impairs liver regeneration. Our aim in this study was to investigate the effect of trimetazidine, known as an anti-ischemic and anti-oxidant agent, on liver regeneration after hepatic blood inflow occlusion. METHODOLOGY: Sprague-Dawley rats were randomized into three groups. Rats in group 1 underwent 65% hepatectomy. Rats in group 2 and 3 were subjected to 15 minutes of hepatic blood inflow occlusion during 65% hepatectomy. Rats were treated with saline (in group 1 and 2) or trimetazidine (in group 3) 30 minutes before operation. Serum level of aspartate transaminase, wet to dry liver weight ratio, and liver injury score in light microscopy were studied for the evaluation of liver injury. Liver regeneration was evaluated by PCNA-labeling index (the percentage of hepatocytes staining for proliferating cell nuclear antigen), mitotic index (the percentage of mitotic hepatocytes), and liver regeneration rate (the percentage of initial liver weight). RESULTS: Rats in group 2 and 3 had significantly higher serum aspartate transaminase level, wet to dry liver weight ratio and injury score than those in group 1 on day 1 posthepatectomy. Except for serum aspartate transaminase level on day 4, these parameters were significantly higher in group 2 than in group 1 and 3 on day 1 and 4. PCNA-labeling index and mitotic index were significantly less in group 2 and 3 than in group 1 on day 1. In contrast to liver regeneration rate, both indices in group 2 were significantly less than those in group 3 on day 1. There were no differences in regeneration parameters between the groups on day 4. Survival rate was significantly higher in group 3 than in group 2. CONCLUSIONS: Fifteen minutes of hepatic blood inflow occlusion caused an injury in the remnant liver, impaired liver regeneration, and decreased survival rate after partial hepatectomy. However, pretreatment with trimetazidine reduced liver injury, and improved liver regeneration and survival rate. For situations where hepatic blood inflow occlusion is planned in major liver resection, trimetazidine pretreatment would be useful strategy to improve postoperative outcome.

Animals↗
PubMed1977

The action of N-hydroxy-2-acetylaminofluorene on the synthesis of ribosomal and poly (A)-RNA in normal and regenerating liver.

Polyribosomal RNA prepared from normal and regenerating liver was chromatographed on poly(U)-Sepharose to obtain rRNA and poly(A)-RNA. Under the conditions employed for labeling the RNA with [5-3H]orotic acid, poly (A)-RNA from regenerating liver represented 1--3% of the total RNA content, and 14--18% of the total radioactivity in polyribosomal RNA at varying times after partial hepatectomy. The specific activity of poly (A)-RNA was elevated by 50% and 30% only at 2 h and 6 h after partial hepatectomy, respectively. Ribosomal RNA synthesis increased 2.5--4 fold at 2--20 h after operation. Treatment of normal or partially hepatectomized rats with N-hydroxy-2-acetylaminofluorene showed a differential dose-dependent effect on rRNA and poly (A)-RNA synthesis with rRNA synthesis being more sensitive to the inhibitory effect of the carcinogen. No change in the poly(A) content was apparent as a result of N-hydroxy-2-acetylaminofluorene treatment.

Animals↗
PubMed1997

Bile acid secretion during synchronized rat liver regeneration.

One major difficulty in interpreting the changes occurring during liver regeneration is the co-existence of non-activated cells and proliferating hepatocytes at all stages of differentiation. The aim of this study was to investigate bile acid (BA) secretion into bile during normal (NLR) and synchronized (SLR) liver regeneration in rats. Regeneration was synchronized by reversible inhibition of ribonucleotide reductase by 10 h treatment with hydroxyurea (HU) shortly after two-third partial hepatectomy. Total BA output as measured by GC-MS increased immediately after partial hepatectomy. This was followed by a further transient enhancement during the next day in the NLR. HU treatment did not significantly modify total BA output, but after releasing synchronized regeneration a marked reduction was observed. This was followed by a recovery to reach values close to those of NLR on day 7 of the regenerative process in SLR. Amidated BA output as measured by HPLC analysis revealed an early enhancement in the proportion of non-conjugated BAs in bile in NLR. However, the profile of conjugated BAs, which was not affected by HU treatment, matched that of total BAs during the first stage of SLR. By contrast, the increase in BA output observed on day 3 of the regenerative process in this group was accounted for by an enhancement in non-conjugated BA secretion. On day 7 of the regenerative process, the proportion of conjugated BA in bile was restored to approximately 100% in this group. Most BA molecules were conjugated with taurine rather than with glycine in all experimental groups, during both NLR and SLR. GC-MS determinations indicated that the magnitude of the cholic acid predominance in all bile samples was significantly modified during liver regeneration. This was increased early after partial hepatectomy and declined toward control values after few (2-3) days. Enhancement in the cholic acid predominance was due to a reduction in the proportion of all other major BAs, above all ursocholic acid and omega-muricholic acid. By contrast, minor BAs in normal control rat bile such as allo-cholic acid were increased during both NLR and SLR, and remained at detectable levels up to day 7. Changes in the proportion of secreted BA species were similar in SLR and NLR except that the early reduction in the proportion of BAs other than cholic acid was more pronounced in SLR and the quantitative importance of the diversity in BA species was recovered earlier in SLR than in NLR. In summary, these results indicate that profound changes in BA secretion during rat liver regeneration do occur. Most of them are probably related to the existence of retro-differentiation/re-differentiation processes which are speeded up by hydroxyurea-induced synchronization of the wave of hepatocyte proliferation.

Animals↗
PubMed1983

[Effects of cianidanol on chronic liver injury induced by carbon tetrachloride and on liver regeneration after partial hepatectomy in rats].

Effects of cianidanol on chronic liver injury induced by prolonged administration of carbon tetrachloride (CCl4) and on liver regeneration after partial hepatectomy of normal liver and CCl4 chronically injured liver were investigated by the measurement of plasma and liver biochemical parameters. Cianidanol increased the total plasma protein and 14C-Leu incorporation into plasma protein, while it reduced the contents of liver cholesterol and triglycerides. In rats with chronically injured liver or regenerating liver after partial hepatectomy of chronically injured liver, cianidanol improved the retention rate of BSP and the content of liver sugar. In rats with chronically injured liver, plasma GPT and GOT activities were reduced with the administration of cianidanol. Cianidanol had no effect on the regeneration rate after partial hepatectomy of normal liver, but it increased the regeneration rate after partial hepatectomy of chronically injured liver. These results suggest that cianidanol has the effect of improving the function of liver cells damaged by CCl4 treatment and of promoting the recovery of cell function to a normal level.

Alanine Transaminase↗
PubMed1992

Rapid and marked induction of hepatocyte growth factor during liver regeneration after ischemic or crush injury.

Liver injuries induced by ischemia or physical trauma are characterized by noninflammatory damage frequently observed in a clinical setting. When the liver of rats was injured by ischemic treatment or physical crushing, necrotic tissue degeneration occurred in several sites of lobulus within 24 hr. Hepatocyte growth factor, a potent mitogen for adult rat hepatocytes in primary culture, was markedly induced in the livers of rats injured by ischemia or physical trauma. In both cases, the hepatocyte growth factor messenger RNA level in the injured liver reached about 10 to 20 times that of the normal level during 12 to 24 hr after liver injury. The increase in hepatocyte growth factor messenger RNA correlated well with the degree of liver damage as evaluated by serum ALT activity in the sera of rats. In situ hybridization showed that hepatocyte growth factor messenger RNA expression occurs in nonparenchymal liver cells, primarily in Kupffer cells of the ischemic liver. After the increase of hepatocyte growth factor messenger RNA in the injured liver, a marked compensatory hepatocyte DNA synthesis occurred 48 to 72 hr after these treatments. These results suggest that hepatocyte growth factor acts as a hepatotropic factor for liver regeneration after noninflammatory liver damage caused by ischemia and physical crush, probably through a paracrine mechanism.

Animals↗
PubMed2004

Changes in splenic volume during liver regeneration.

Little is known about the relation between liver regeneration and splenic size. We monitored serial changes in liver and spleen volumes using computed tomography in 24 patients with biliary cancer who underwent right hepatectomy or more extensive liver resection following portal vein embolization (PVE). Nonembolized hepatic segments increased in volume from 316 +/- 97 cm3 (34% +/- 8% of total liver volume) before PVE to 410 +/- 115 cm3 (44% +/- 8%) after PVE. The volume of nonembolized hepatic segments (i.e., remnant liver) increased to 617 +/- 111 cm3 (59% +/- 10% of total liver volume before PVE) 14 days after hepatectomy and then increased slowly to reach 795 +/- 231 cm3 (76% +/- 16%) 1 year after hepatectomy. Splenic volume increased from 87 +/- 29 cm3 before PVE to 104 +/- 38 cm3 (119% +/- 17% of original volume) after PVE. Splenic volume increased to 137 +/- 65 cm3 (155% +/- 40%) by 14 days after hepatectomy and to 155 +/- 67 cm3 (179% +/- 41%) by 28 days after hepatectomy, with no further change at 1 year after hepatectomy (153 +/- 92 cm3; 174% +/- 79%). The rate of increase in splenic volume within the first 14 days after hepatectomy was 2.7 +/- 3.6 cm3/day, correlating well with increases in remnant liver volume ( r = 0.64, p = 0.0006). These data indicate that the spleen is enlarged during liver regeneration, suggesting that the liver and spleen share certain common growth regulatory mechanisms.

Aged↗
PubMed1991

Human liver regeneration after major hepatectomy. A study of liver volume by computed tomography.

Regeneration of the remnant liver after major hepatectomy in humans was studied by computed axial tomography (CT) in 12 noncirrhotic and five cirrhotic patients. Liver volumes were measured by abdominal CT 3 days, 10 days, 3 months, 6 months, 1 year, and 1.5 years after resection. Of the 17 patients, liver remnant volume was increased in 21.2% +/- 6.7% and 30.6% +/- 12.7% at 3 months and 6 months after resection, respectively. Noncirrhotic livers were 28.4% +/- 9.5% and 48.4% +/- 17.8% larger at 3 and 6 months. For cirrhotic livers, the increase was 8.5% +/- 3.6% and 12.9% +/- 4.5%. In five patients with right hepatectomy (65% resection), the liver remnant volumes were increased 38.4% +/- 11.7%, 48.0% +/- 16.2% and 95.1% +/- 4.5% at 3 months, 6 months, and 1 year after resection, respectively. In seven patients with right partial hepatectomy (30% to 35% resection), the percentages were 7.4% +/- 3.2%, 21.8% +/- 8.4%, and 63.9% +/- 18.3% and in five patients with left lateral segmentectomy (15% resection), they were 15.6% +/- 8.2%, 27.8% +/- 12.2%, and 33.0% +/- 14.5% 3 months, 6 months, and 1 year after resections, respectively. Noncirrhotic livers showed better regeneration than cirrhotic livers. Complete regeneration took about 1 year. The noncirrhotic liver that underwent right lobectomy also needed 1 year to double its postresection volume.

Adult↗
PubMed1997

Ki-67 expression during rat liver regeneration after partial hepatectomy.

Antibodies to the cell-cycle-associated Ki-67 protein have been widely used for more than a decade as markers of proliferative cells. The prototype antibody Ki-67 reacted only with snap-frozen human tissue, but a novel antibody, MIB-1, was able to detect the Ki-67 antigen in paraffin wax-embedded human tissue. The ability of MIB-5, a novel antibody reactive with the rat equivalent Ki-67 protein, to immunohistochemically detect cycling parenchymal and littoral cells in the regenerating rat liver is reported. Rats underwent a standard two-thirds partial hepatectomy (PH), and groups of three animals were killed at intervals for up to 192 hours after PH. DNA synthesis was monitored by flash labeling with bromodeoxyuridine, and the response was as expected with a significant upsurge in hepatocyte labeling at 16 to 17 hours after PH. On the other hand, MIB-5 labeled a relatively constant percentage of hepatocytes (4%-8%) during the first 16 hours after PH, before a large proportion became labeled, also at 17 hours. The temporal pattern of MIB-5 labeling was similar to that of bromodeoxyuridine labeling, although, as expected, MIB-5 indices were higher. Semiquantification of Ki-67 messenger RNA (mRNA) levels by reverse-transcription polymerase chain reaction showed modest (fourfold to fivefold) increases in abundance during the first 12 hours after PH, but then levels increased dramatically to be at least 15-fold those of intact liver at 36 hours after PH. Much higher than normal levels of Ki-67 mRNA persisted throughout the period of study and even at 96 hours after PH they were still ninefold greater than normal. This study has shown the usefulness of the MIB-5 antibody to monitor proliferation in the rat liver, and furthermore, the pattern of expression of both the mRNA and the protein suggest that the Ki-67 protein, with hitherto unknown function, is more abundant in DNA synthesis and mitosis than in the early or even very late first G1 phase.

Animals↗
PubMed1979

Metabolic alterations of liver regeneration. XV. Cadmium-mediated depression of thymidine and thymidylate kinase induction in rats.

Cadmium administered shortly before or after partial hepatectomy blocks in a dose-dependent manner the increase of thymidine and thymidylate kinase activities in regenerating rat livers. The effect of cadmium can be partially antagonized by simultaneous zinc administration. The intraperitoneal injection of cadmium is more effective than its subcutaneous administration. While there are in vitro differences in the sensitivity of thymidine kinase and thymidylate kinase towards Cd2+-, Zn2%- and Cu2+-ions, both enzymes are equally depressed following their in vivo administration. Cadmium displays the highest inhibitory activity and resembles in this respect beryllium [1].

Animals↗
PubMed1977

Guanylate cyclase activity and cyclic nucleotide concentrations during liver regeneration after experimental injury.

Cyclic nucleotide concentrations and guanylate cyclase activity were measured in regenerating rat liver. Previous work has shown that in livers of partially hepatectomized rats the activity of a membrane-bound guanylate cyclase increases considerably during the early replicative phase [Kimura & Murad (1975) Proc. Natl. Acad. Sci. U.S.A.72, 1965-1969; Goridis & Reutter (1975) Nature (London) 257, 698-700]. Over the same time period after partial hepatectomy, increased tissue concentrations of cyclic GMP were found when the rats were killed under pentobarbital anaesthesia, but not when anaesthesia was omitted. The results obtained on hepatectomized livers were compared with the changes in guanylate cyclase activity and cyclic nucleotide concentrations during the response to galactosamine treatment. Here, a peak of guanylate cyclase activity and of cyclic GMP concentrations occurred at 8h, that is before the beginning of the proliferative response. Both parameters were normal at the time of increased DNA synthesis. There does not, therefore, seem to be a consistent correlation between changes in guanylate cyclase activity or concentrations of cyclic GMP and an increase in liver DNA synthesis. A modest rise in cyclic AMP concentrations was found, however, in livers of galactosamine-treated rats, which was coincident with the time of DNA synthesis.

Animals↗
PubMed1985

Re-utilization of pyrimidine nucleotides during rat liver regeneration.

The changes in the specific radioactivities of the pool of total acid-soluble uridine nucleotides and of uridine and cytidine components of total cellular and nuclear RNA were monitored in regenerating rat liver for 12 days after partial hepatectomy. Evidence is presented for the re-utilization of pyrimidine nucleotides derived from cytoplasmic RNA degradation for the synthesis of new RNA. The extent of recycling was assessed and the true rate of rRNA turnover determined more accurately. The reutilization of the uridine components of RNA was 7.0%/day during the proliferative and 3.2%/day during the post-proliferative phase, whereas that of the cytidine nucleotides was more pronounced (9.6%/day and 18.1%/day respectively). The results reveal the existence of partial compartmentalization of pyrimidine ribonucleoside triphosphate pools in the nucleus and cytoplasm of rat liver cells.

Animals↗