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PubMed1989

Famotidine does not inhibit liver regeneration.

The H2-blockers, cimetidine and ranitidine, are reported to inhibit liver regeneration. In this work, the effects of a new powerful H2-receptor antagonist, famotidine, on liver regeneration were studied in rats. The animals were divided into three groups: group I in which a standard two-thirds hepatectomy was performed, group II in which the rats were treated with famotidine (intramuscular dose of 0.8 mg/kg body weight) on the day of operation and 24 and 48 h after hepatectomy, and group III in which the animals were intramuscularly injected with a larger dose of famotidine (1.2 mg/kg body weight) in the same way as group II. The histology and mitotic index of remnant livers and serum levels of aminotransferase and albumin were examined from 24 h to 10 days after the operation. The treatment with famotidine (groups II and III) did not inhibit hepatocyte mitosis but, on the contrary, raised the index on day 3 after hepatectomy when compared with the controls (group I). The albumin synthesis was well preserved in the famotidine-treated animals. The noninhibitory effects of famotidine on liver regeneration are discussed.

Alanine Transaminase↗
PubMed1991

Nuclear protein kinases in rat liver: evidence for increased histone H1 phosphorylating activity during liver regeneration.

Comparison of protein kinase activity in normal and regenerating rat liver nuclei indicates that exogenous histone H1 is hyperphosphorylated in 22-h regenerating nuclei. The protein kinase involved is not sensitive to protein kinase A inhibitor, is inhibited by staurosporine and by an anti-PKC polyclonal antibody, utilizes only ATP, and also phosphorylates the C-terminal fragment of histone H1. These data suggest that protein kinase C is responsible for the observed effects, in agreement with the presence of this enzyme in normal and regenerating nuclei demonstrated by immunoblotting.

Adenosine Triphosphate↗
PubMed1975

Possible interactions between the urea cycle and synthesis of pyrimidines and polyamines in regenerating liver.

Ornithine levels rise progressively in the liver of partially hepatectomized rats, probably as a consequence of the increased flow of metabolites through the urea cycle. Ammonia and urea concentrations in the blood and liber of partially hepatectomized animals are not significantly different from those of sham-operated rats. However, in regenerating livers, the ability to remove ammonia from the blood is close to its maximal limit. Ammonia overload leads to the production of large amounts of orotic acid and causes a marked elevation of hepatic ornithine decarboxylase activity. Among the pyrimidine precursors dihydroorotic acid injections increase the activity of the enzyme while orotic acid is without effect. A peak of labeled material that corresponds to dihydroorotic acid was identified by partition chromatography of acid-soluble extracts of livers of partially hepatectomized rats previously given injections of [14-C2 bicarbonate. The labeling of dihydroorotic acid from [14-C] bicarbibate is increased in the liver of rats given injections of ornithine. Despite the difficulties involved in studies of ornithine decarbozylase activity in vivo, our results suggest that mutual interactions between urea, pyrimidine, and polyamine synthesis take place during liver regeneration.

Adrenalectomy↗
PubMed2006

Reactive oxygen species derived from NADPH oxidase system is not essential for liver regeneration after partial hepatectomy.

BACKGROUND: There is suggestive evidence that reactive oxygen species may play a role in the initiation of liver regeneration via a kupffer cell-mediated mechanism involving TNFa and NF-kappa B. In mammalian cells, a major source of reactive oxygen species derives from the membrane-bound NADPH oxidase system (no protein de novo synthesis is required) and it is known that the low levels of oxidants produced through NADPH oxidase play a role in liver cell proliferation because of peroxisome proliferators. METHODS: We used knockout mice lacking Cybb: subunit of NADPH oxidase to determine whether signaling at the start of liver regeneration after partial hepatectomy (PH) involves reactive oxygen species produced through NADPH oxidase and to analyze in more detail the abnormalities caused by lack of its component, which is required for the initiation of liver regeneration. RESULTS: Lack of Cybb had little effect on NF-kappa B and STAT3 binding, and no effect in TNFa and interleukin-6 production after PH. Cybb KO mice had normal liver structure and similar levels of hepatocyte DNA replication as those of wild type mice. CONCLUSIONS: We conclude that NADPH oxidase is not necessary for liver regeneration after PH. It is likely that there is a potential pathway not including NADPH oxidase to activate NF-kappa B and STAT3 binding for the initiation of liver regeneration after PH.

Animals↗
PubMed2005

Donor outcome and liver regeneration after right-lobe graft donation.

Sufficiently detailed information on donor safety and the liver regeneration process following right-lobe living donation has been unavailable, so we evaluated donor outcome and liver regeneration in 13 males and 14 females (39.0 +/- 14.8 years old) who provided 27 right-lobe grafts without the middle hepatic vein. Preoperative total liver volume (TLV), graft volume, and postoperative changes in residual liver volume (RLV) were measured by volumetric computed tomography. Histological steatosis of the liver was graded as none, minimal (< or =10%), and mild (11-30%). The median follow-up period was 337 days. Estimated graft volume and actual graft weight were linearly correlated (Y = 177.85 + 0.795X, R(2) = 0.812, P < 0.0001). Graft-to-recipient weight ratio was 1.08 +/- 0.19%. Four donors had postoperative complications, but they resolved in response to conservative treatment. Postoperative hospital stay was 15.2 +/- 5.5 days. Peak liver enzyme values were significantly higher in donors with mild steatosis (n = 7) than without steatosis (n = 16) (P < 0.05). Donor RLV was 40.8 +/- 6.6% of original TLV at surgery, 79.8 +/- 12.0% by 6 months, and 97.2 +/- 10.8% by 12 months. At 3 months the liver of the older donors (> or =50 years) had grown significantly more slowly than in younger donors (70.4 +/- 9.2% vs. 79.3 +/- 9.6%, P = 0.0391). In conclusion, right hepatectomy without middle hepatic vein of living donors is a safe procedure with acceptable morbidity, and the residual liver regenerated to its preoperative size by 1 year. However, meticulous care should be taken in donors with liver steatosis and aged donors.

Adult↗
PubMed2002

Bcl-2 expression delays hepatocyte cell cycle progression during liver regeneration.

Bcl-2 is the prototype of a family of genes that prevent apoptosis. However, several reports indicate that Bcl-2 may also act as a cell cycle modulator. In several human tumors, Bcl-2 expression correlates with a more favorable prognosis and lower tumor proliferative activity. We have shown that Bcl-2 expression delays liver tumor development in transgenic mice even when the gene is turned on shortly before the time of tumor development. We hypothesized that Bcl-2 may delay liver tumorigenesis by interfering with hepatocyte proliferation. To test whether Bcl-2 expression may act on hepatocyte replication we studied liver regeneration in Bcl-2 transgenic mice and wild-type littermates. DNA replication was delayed by approximately 8 h in Bcl-2 transgenic mice compared to the timing of the response in wild-type littermates. Cyclin D expression showed no alterations in the regenerating liver of Bcl-2 transgenic mice. In contrast, there was a delay in the expression of p107, cyclin E and in the activity of cyclin E/cdk 2 activity. These results show that Bcl-2 expression delays cell cycle progression in hepatocytes and suggests that it acts at a step involving cyclin E and p107.

Animals↗
PubMed1990

Immediate-early gene expression differs between regenerating liver, insulin-stimulated H-35 cells, and mitogen-stimulated Balb/c 3T3 cells. Liver-specific induction patterns of gene 33, phosphoenolpyruvate carboxykinase, and the jun, fos, and egr families.

Immediate-early genes, whose expression increases independent of de novo protein synthesis during the transition from quiescence to proliferation, are postulated to play important regulatory roles in the growth response. The complement of immediate-early genes expressed must depend on the milieu of preexisting transcription factors in the quiescent cell as well as the type of mitogenic stimulation and, thus, may differ between cell types. We have begun characterizing the immediate-early response in regenerating liver and insulin-stimulated Reuber H-35 hepatoma cells in comparison with previously published results from mitogen-stimulated Balb/c 3T3 fibroblasts. The proliferating H-35 and regenerating liver cells maintain their similarity to quiescent liver as demonstrated by their continued production of the liver-specific albumin, CCAAT/enhancer binding protein, and phosphoenolpyruvate carboxykinase messenger RNAs (mRNA). Surprisingly, the phosphoenolpyruvate carboxykinase gene, which undergoes down-regulation in insulin-treated H-35 cells, was cloned by differential screening of a subtraction-enriched regenerating liver cDNA library and is an immediate-early gene in regenerating liver. H-35 cells treated with either insulin or phorbol 12-myristate 13-acetate express elevated levels of the jun genes, and phorbol 12-myristate 13-acetate pretreatment fails to abolish the insulin response, indicating that it does not depend on protein kinase C. jun family gene expression in regenerating liver differs from that in mitogen-treated fibroblasts in that the time course of expression of c-jun and junB is prolonged, and junD mRNA levels distinctly increase. Additionally, although c-fos and egr-1 mRNAs are expressed at elevated levels in stimulated liver cells, fos-B, fra-1, and egr-2 are not, which suggests that factors in addition to the serum response factor participate in the regulation of immediate-early gene induction. Interestingly, gene 33, which was cloned from a regenerating liver cDNA library by differential screening and lacks a recognizable serum response element, functions as an immediate-early gene in regenerating liver and in mitogen-treated H-35 and Balb/c 3T3 cells. These results suggest that gene 33 participates in the transition from quiescence to proliferation in many mitogen-treated cells in addition to its previously reported involvement in hormone responses. Overall, the results presented here suggest that the immediate-early response varies considerably between regenerating liver and mitogen-stimulated fibroblasts and could involve multiple, preexisting, tissue-specific, transcription-activating proteins.

Animals↗
PubMedDate not supplied

[Study of cytoplasmic RNA in tissues of the rat, regenerating liver and in liver of rats with hepatoma PC-1].

Cytoplasmic RNA of the rat regenerating liver and liver of rats with hepatoma PC-1 is separated into five fractions on the column of kieselgur with methylated albumin (MAK). Studies in the nucleotide composition showed that certain fractions of cytoplasm RNA are ribosomal and messenger RNA. The highest amount of radioactive precursor is incorporated into messenger RNA of the rat regenerating liver and liver of the rats with hepatoma PC-1 which is eluated from the column by 0.2% solution of sodium dodecyl sulphate at 37 degrees C (third fraction). Actinomycin D in doses inhibiting appearance of characteristic proteins in the blood serum of rats with the regenerating liver and heaptoma PC-1 blocks almost completely biosynthesis of ribosomal RNA eluated from the MAK column in the gradient of sodium chloride (second fraction), and that of messenger RNA, eluated by sodium dodecyl-sulphate at 37 degrees C (third fraction).

Animals↗
PubMed1996

Liver regeneration in fulminant hepatitis as evaluated by serum transforming growth factor alpha levels.

Transforming growth factor alpha (TGF alpha) is supposed to act as a mitogen for hepatocytes in an autocrine manner in vitro and in vivo. Retarded liver regeneration is a possible reason for poor prognosis of fulminant hepatitis (FH). We analyzed serum TGF alpha levels in patients with FH and patients with acute nonfulminant hepatitis (AH). Also, the relation of those levels to serum hepatocyte growth factor (HGF) levels and their changes after glucagon-insulin (G-I) therapy were studied. Maximal serum TGF alpha levels achieved in each case after admission until recovery from disease or death were correlated positively with maximal serum alanine transaminase (ALT) and total bilirubin levels in patients with AH, but negatively with maximal total bilirubin levels in patients with FH. Maximal serum TGF alpha levels in patients with FH were significantly higher in survivors than in nonsurvivors. Maximal serum HGF levels were positively correlated with maximal serum TGF alpha levels in patients with AH, but not in patients with FH. Multiple regression analysis indicated that G-I therapy was related to the increment of serum TGF alpha levels in patients with FH. These results suggest that serum TGF alpha levels are increased in accordance with liver regeneration after necrosis in patients with AH, but such liver regeneration may be retarded, depending on the extent of liver damage in patients with FH. G-I therapy seems to stimulate liver regeneration after liver damage. The possible contribution of TGF alpha and HGF to liver regeneration merits consideration for recovery from AH.

Drug Therapy, Combination↗
PubMed2002

Hepatocyte growth factor and c-Met inhibition by hepatic cell hypoxia: a potential mechanism for liver regeneration failure in experimental cirrhosis.

Hepatic resection in cirrhotic patients is associated with impaired liver regeneration and poor clinical outcome. Because experimental cirrhosis is associated with hepatic cell hypoxia, we herein investigated whether hypoxia might alter the mechanisms of liver regeneration in the cirrhotic liver. Cirrhosis was induced by diethylnitrosamine in rats. Immunohistochemistry was performed to assess hepatocellular hypoxia and proliferation 24 hours after a two-thirds partial hepatectomy (PH) in cirrhotic and control rats. Cultured hepatocytes and myofibroblastic hepatic stellate cells were submitted to hypoxia using anaerobic jars. Hepatocyte growth factor (HGF) and c-Met expressions were determined by reverse transcriptase-polymerase chain reaction, Northern blot, and Western blot. In control rats, hypoxia was restricted to perivenular hepatocytes, and PH induced a marked increase in hepatocyte proliferation and in liver HGF expression, whereas c-Met expression remained unchanged. In cirrhotic rats, hypoxia was detected virtually in all of the hepatocytes, and PH induced no significant change in hepatocyte proliferation and in liver HGF expression, whereas c-Met expression was decreased as compared to normal livers. In vitro, the expression of HGF in myofibroblastic hepatic stellate cells and of c-Met in hepatocytes underwent a dramatic decrease under hypoxia. Our results suggest that hepatocellular hypoxia causes inhibition of HGF (and of c-Met)-mediated proliferation and thereby might contribute to liver regeneration failure in cirrhotic liver.

Animals↗
PubMed2003

Leptin-specific mechanisms for impaired liver regeneration in ob/ob mice after toxic injury.

BACKGROUND & AIMS: Profound impairment of liver regeneration in rodents with dysfunctional leptin signaling has been attributed to non-alcohol-induced fatty liver disorders (NAFLD). Our aim was to establish whether defective liver regeneration in ob/ob mice is a direct consequence of leptin-dependent, intracellular signaling mechanisms controlling cell-cycle regulation in hepatocytes. METHODS: After exposure to a single hepatotoxic dose of (CCl(4)), the regenerative response to hepatic injury was studied in leptin-deficient ob/ob and control mice. The effects of leptin supplementation (100 microg x kg(-1) x day(-1)) were examined. We assessed entry into and progression through the cell cycle and activation of key signaling intermediates and transcriptional regulators. RESULTS: CCl(4)-induced liver injury was equally severe in ob/ob and control mice. In leptin-deficient mice, it was associated with exaggerated activation of NF-kappa B and STAT3 during the priming phase, abrogation of tumor necrosis factor (TNF) and interleukin (IL)-6 release at the time of G1/S transition, and failure of hepatocyte induction of cyclin D1 and cell cycle entry. Leptin replacement corrected these defects in ob/ob mice by restoring TNF and IL-6 release and inducing cyclin D1. Hepatocytes entered S phase and progressed, as in wild-type mice, to vigorous mitosis and normal hepatic regenerative response. In ob/ob mice, low doses of TNF before CCl(4) also were associated with restitution of TNF release and proliferative capabilities. CONCLUSIONS: Impaired liver regeneration in ob/ob mice is caused by leptin deficiency. We propose that altered cytokine production in ob/ob mice is part of the mechanisms responsible for impaired proliferation in response to hepatic injury.

Animals↗
PubMed2005

Overexpression of NK2 inhibits liver regeneration after partial hepatectomy in mice.

AIM: To investigate the in vivo effects of NK2 on liver regeneration after partial hepatectomy (PH). METHODS: Survival after PH was observed with 21 NK2 transgenic mice and 23 wild-type (WT) mice over 10 d. Liver regeneration was analyzed using histology and immunohistochemistry. Expressions of genes were analyzed using Northern blot analysis, immunoprecipitation and immunoblotting, and reverse transcriptase polymerase chain reaction assay. Kaplan-Meier method and the log-rank test were used for analyzing the survival after PH. Differences in the results of immunohistochemistry and percentage of liver regeneration was determined by the Student's t-test. RESULTS: More than half of NK2 transgenic mice died within 48 h after PH. After PH, increased deposition of small lipid droplets in hepatocytes was evident and hepatic proliferation was inhibited in NK2 transgenic mice. The hepatic expression and kinase activity of HGF receptor, c-Met, were unchanged among WT mice and NK2 transgenic mice after PH. The expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in liver tissues were prolonged in NK2 transgenic mice that died after PH. CONCLUSION: Our findings indicate that over-expression of NK2 inhibits liver regeneration after PH.

Animals↗
PubMed2005

Impaired proliferation of non-parenchymal cells participates in an impairment of liver regeneration in db/db mice.

In this study, we examined the possibility that impaired proliferation of non-parenchymal cells affects in an impairment of liver regeneration in db/db mice, which are congenitally deficient in receptors for leptin. Liver regeneration after a two thirds partial hepatectomy (2/3 PH) was impaired in 10-week-old female db/db mice. The proliferation of both hepatocytes and non-parenchymal cells estimated from a bromodeoxyuridine (BrdU) labeling index was suppressed, and the protein expression of vascular endothelial growth factor was blocked in db/db mice. Although the extent of fatty change and the level of epidermal growth factor receptor protein expression in the liver were improved in 5-week-old db/db mice, the regeneration of liver was impaired after 2/3 PH in both 5- and 10-week-old db/db mice. These results suggested that suppressed proliferation of non-parenchymal cells contributes to the impairment of liver regeneration in db/db mice. As leptin has also the angiogenic effect, the angiogenic inhibitor FR-118487 was administered to ICR mice to examine liver regeneration after 2/3 PH, and the rate of regeneration was affected. In conclusion, it is suggested that the suppressed proliferation of non-parenchymal cells contributes to the impairment of liver regeneration probably through a disrupted angiogenesis in db/db mice.

Angiogenesis Inhibitors↗
PubMed1987

Purification and characterization of thymidylate synthetase from rat regenerating liver.

Thymidylate synthetase (EC 2.1.1.45) from rat regenerating liver has been purified over 5000-fold to apparent homogeneity by a procedure involving two affinity methods. Molecular weight of the native enzyme was found to be about 68,000, as determined by gel filtration. Electrophoresis in polyacrylamide gels containing sodium dodecyl sulfate yielded a single band of molecular weight of 35,000, suggesting that thymidylate synthetase is a dimer of very similar or identical subunits. The Michaelis constants for deoxyuridylate (dUMP) and (+/-)L-5,10-methylenetetrahydrofolate are 6.8 microM and 65 microM, respectively. Reaction kinetics and product inhibition studies reveal the enzymatic mechanism to be ordered sequential. 5-Fluoro-dUMP, halogenated analog of the nucleotide substrate is a competitive inhibitor of the enzyme, with an apparent Ki value of 5 nM. Amethopterin, analog of the cofactor is also a competitive inhibitor with an apparent Ki value of 23 microM.

Animals↗
PubMed1983

[Possible role of biliverdin as an initiator of liver regeneration].

Biliverdin has been proposed as the biological signal that triggers liver regeneration after partial hepatectomy, since a transitory increase of plasma levels is found shortly after partial hepatectomy. We have carried out a detailed study to establish the feasibility of such a hypothesis. When biliverdin is administered i.p., it binds to albumin. This became evident by electrophoresis and affinity chromatography. Biliverdin disappears from the peritoneal cavity following a 1st order kinetics (t 1/2 = 40 min, K = 0.0175 min -1). Biliverdin reductase activity in the peritoneal exudate was high (1.04 mumol Bv min -1/mg protein), and very small amounts of biliverdin in comparison to the administered dose were found in plasma. However, unconjugated bilirubin level was high in plasma and the conjugated bilirubin in bile flux reached its maximum 90 min after administration. On the basis of blood elimination of biliverdin when administered intravenously (t 1/2 = 11 min, K = 0.068 min -1), a series of experiments was designed to reproduce the levels of plasma biliverdin as found shortly after partial hepatectomy. Our results showed a total absence of liver regeneration. There is, however, increase of the mitotic index if biliverdin is administered intraperitoneally. This effect is not directly related to biliverdin but to unspecific (?) stimulation of peritoneal cavity since the same effect was obtained after administration of unrelated substances (diatomaceous earth, killed bacteria). The mitotic figures did not incorporate 3H-thymidine, and it is suggested that those cells came from a G2 blocked quiescent cell population in liver. We therefore conclude that biliverdin is not the physiological trigger of liver regeneration.

Albumins↗
PubMedDate not supplied

Serum 7alpha-hydroxycholesterol levels during liver regeneration after hepatectomy in humans.

BACKGROUND/AIMS: Changes in bile acid synthesis during liver regeneration after hepatectomy is little known in humans. Since it has been reported that the serum 7 alpha-hydroxycholesterol levels reflect the hepatic bile acid synthesis and that the determination of bile acid synthesis is useful to assess the liver regeneration rate, we determined the serum 7 alpha-hydroxycholesterol level during liver regeneration after hepatectomy in clinical patients. METHODOLOGY: The serum 7 alpha-hydroxycholesterol levels were determined by gas-liquid chromatography-mass spectrometry-selected ion monitoring method before and on days 1, 3, 5, 7, 14 and 21 after hepatectomy in twenty consecutive patients. RESULTS: The 7 alpha-hydroxycholesterol levels became lower between days 1 and 7, were increased on day 14, and then decreased on day 21 after hepatectomy. The patients with preoperative external biliary drainage showed a higher serum 7 alpha-hydroxycholesterol level than those without biliary drainage before hepatectomy. The former showed lower serum 7 alpha-hydroxycholesterol levels than the latter throughout the 21 days after hepatectomy. In patients whose liver resection rate was more than 50%, the serum 7 alpha-hydroxycholesterol levels were kept lower until 21 days after hepatectomy compared with those whose liver was excised less than 50%. CONCLUSIONS: It is concluded that the patients who had preoperative biliary drainage or major hepatic resection seem to have less hepatic reserve capacity for bile acid synthesis after hepatectomy.

Bile Acids and Salts↗
PubMed2001

Blood transfusion causes deterioration in liver regeneration after partial hepatectomy in rats.

BACKGROUND: This study investigated the effects of blood transfusion on liver regeneration and function after hepatectomy in rats. METHODS: Inbred male Sprague-Dawley rats underwent a sham operation or a 70% hepatectomy (PHx) and were randomly divided into seven groups according to transfusion type: groups I and II underwent a sham operation and received saline (I) or whole blood (II). Groups III to VII underwent PHx with saline (III), whole blood (IV), irradiated/leukocyte-depleted whole blood (V), plasma (VI), or autologous blood (VII). The liver regeneration rate, proliferating cell nuclear antigen (PCNA) labeling index, serum aspartate aminotransferase, alanine aminotransferase, purine nucleoside phosphorylase (PNP) activity, hepatocyte growth factor (HGF), and activated transforming growth factor beta1 (TGF-beta(1)) were measured 6 and 24 h and 5 days after PHx. RESULTS: The liver regeneration rate and PCNA labeling index were lower in groups IV and V than in the other groups. Serum liver enzymes 6 h after PHx were worst in groups IV and V. PNP activity increased most in group IV, 6 and 24 h after PHx. The HGF values 6 h after PHx in all the transfused groups were lower than in group III. The activated TGF-beta(1) level 6 h after surgery was highest in group IV. CONCLUSION: Whole blood or irradiated/leukocyte-depleted whole blood impaired liver regeneration after PHx, probably through the production of activated TGF-beta(1) and HGF outside the liver, and plasma or autologous blood reduced the deleterious effects.

Animals↗