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PubMed1986

Proto-oncogene expression in regenerating liver is simulated in cultures of primary adult rat hepatocytes.

Proto-oncogene fos mRNA levels are rapidly and transiently elevated 12-fold in regenerating liver 10-60 min following partial hepatectomy. This response, and the induction of fos protein synthesis, has been simulated qualitatively and quantitatively in long term primary cultures of quiescent adult rat hepatocytes where proliferative transitions can be initiated directly in serum-free medium by known hepatocyte mitogens like epidermal growth factor. Expression of a second proto-oncogene, c-rasH, in proliferatively activated hepatocyte cultures between 6 and 24 h also simulates the delayed hepatic response that occurs in vivo following partial hepatectomy. These results suggest that sequential proto-oncogene expression during liver regeneration is caused directly by hepatocellular interactions with specific mitogens. In addition, a role for monovalent cations in the regulation of hepatocyte gene expression is implicated from findings that Na+ deprivation inhibits induction of fos expression in cultured hepatocytes by epidermal growth factor under chemically defined conditions.

Animals↗
PubMed1980

The modification of rat liver regeneration by carcinogens and its reflection by extrahepatic tissues.

Liver regeneration is distinctly influenced by the treatment of male Sprague-Dawley rats with 2-acetylaminofluorene or N-methyl-N-nitrosourea on three successive days immediately prior to partial hepatectomy. The latter compound modulates the restorative liver growth, whereas it is strongly inhibited by the hepato-carcinogen 2-acetylaminofluorene. According to their influence on the regenerating liver, both carcinogens delay the post-operative decrease as well as the recovery of the physiological cell renewal in the jejunal and esophageal epithelium. Beside this, the circadian mitotic fluctuation of the esophagus is also altered by the carcinogens after partial hepatectomy like that of the regenerating liver. In contrast to the behaviour of the jejunum and the esophagus, the adrenocortical cell division is temporally elevated by the growth stimulus after partial hepatectomy. This effect is also found after carcinogen pretreatment only. For that reason one can assume that carcinogens produce a growth stimulating response like partial hepatectomy, which is displayed by an increased cell replication in the adrenal cortex. Possibly this phenomenon reflects common systemic mechanisms which indicate the promotory action of partial hepatectomy and chemical promotors as well as that of carcinogens.

2-Acetylaminofluorene↗
PubMed1999

Phenobarbital in comparison with carbon tetrachloride and phenobarbital-induced cirrhosis in rat liver regeneration.

BACKGROUND: The simultaneous administration of carbon tetrachloride (CCl4) and phenobarbital in the rat produces one of the most common experimental models of liver cirrhosis. As phenobarbital also has a hepatotrophic effect, its role in liver regeneration following partial hepatectomy (HTX) is not elucidated. PURPOSE: To examine the effect of long-term administration of phenobarbital in liver regeneration after HTX with regard to CCl4-induced cirrhotic rat model. Materials and Methods. The liver regeneration following HTX in phenobarbital-treated rats (PB rats) was compared to that seen in cirrhotic rats (LC rats), induced by oral gavage of CCl4 and phenobarbital, and normal rats. The effect of the withdrawal of phenobarbital was also examined. Liver regeneration was estimated 24 h after the HTX by measuring the liver weight, the DNA content in the liver, and [3H]thymidine incorporation into the DNA. RESULTS: Treatment with CCl4 and phenobarbital caused liver deformity, and the highest percentage of liver weight regeneration was seen in LC rats with this deformity, even though [3H]thymidine incorporation into the DNA was impaired in this group. Phenobarbital had a hepatotrophic effect, but its withdrawal caused a decrease in liver mass and cessation of body weight gain. The change in the DNA content 24 h after HTX was negative in PB rats. CONCLUSIONS: Liver regeneration could not be estimated using liver or body weight in the PB or LC rat model. [3H]Thymidine incorporation into the DNA was reliable indicator of liver regeneration in the different liver states during the early stage after HTX. Although the DNA content with respect to total liver mass was obscured due to liver inflation in PB rats, [3H]thymidine incorporation into the DNA between PB rats and normal rats was similar.

Animals↗
PubMed2004

Negative regulation of liver regeneration by innate immunity (natural killer cells/interferon-gamma).

BACKGROUND AND AIMS: Hepatic lymphocytes are composed mainly of natural killer (NK) cells and NKT cells, which play key roles in innate immune responses against pathogens and tumors in the liver. This report analyzes the effects of activation of innate immunity by viral infection or the toll-like receptor 3 (TLR3) ligand on liver regeneration. METHODS: The partial hepatectomy (PHx) method was used as a model of liver regeneration. Murine cytomegalovirus (MCMV) infection and the TLR3 ligand polyinosinic-polycytidylic acid [poly(I:C)] were used to activate innate immunity. RESULTS: NK cells are activated after PHx, as evidenced by producing interferon (IFN)-gamma. Infection with MCMV or injection of poly(I:C) further activates NK cells to produce IFN-gamma and attenuates liver regeneration in the PHx model. Depletion of NK cells or disruption of either the IFN-gamma gene or the IFN-gamma receptor gene enhances liver regeneration and partially abolishes the negative effects of MCMV and polyI:C on liver regeneration, whereas NKT cells may only play a minor role in suppression of liver regeneration. Adoptive transfer of IFN-gamma +/+ NK cells, but not IFN-gamma -/- NK cells, restores the ability of polyI:C to attenuate liver regeneration in NK-depleted mice. Finally, administration of polyI:C or IFN-gamma enhances expression of several antiproliferative proteins, including STAT1, IRF-1, and p21cip1/waf1 in the livers of partially hepatectomized mice. CONCLUSIONS: Our findings suggest that viral infection and the TLR3 ligand negatively regulate liver regeneration via activation of innate immunity (NK/IFN-gamma), which may play an important role in the pathogenesis of viral hepatitis.

Adoptive Transfer↗
PubMed1995

Site-specific protein synthesis in liver regeneration determined by PET.

Site-specific regeneration of the liver after 70% partial hepatectomy was investigated noninvasively in terms of protein synthesis using PET with L-[methyl-11C]methionine in a living animal. Protein synthesis in rat liver at 24 hr after partial hepatectomy did not occur uniformly in the whole liver but intensely in the middle part of the regenerating organ in comparison with the other parts. The activity was significantly low at the posterior aspect of the liver. On the other hand, site-specific protein synthesis was not observed in normal liver. These results were confirmed by bioimaging analyzer system (BAS) analysis, an invasive method that indicates radioactivities of precise intrahepatic sites. DNA synthesis in regenerating liver was also monitored with [2-14C]thymidine and analyzed by BAS 24 hr after 70% hepatectomy. Site-specific DNA synthesis in regenerating liver corresponding to the protein synthesis was also observed by BAS analysis. These results indicate that liver regeneration occurs intensely in the middle part of the liver and that PET enables noninvasive in vivo biochemical analysis.

Animals↗
PubMed1997

Acute portal hypertension reflecting shear stress as a trigger of liver regeneration following partial hepatectomy.

The concept of injury in liver regeneration after partial hepatectomy (PHx), and the reason hepatocytes that have not been directly injured regenerate, remain unclear. It is known that shear stress resulting from blood flow plays an important role in the mechanism of remodeling blood vessels, and portal pressure reflects shear stress. This study was conducted to determine whether acute portal hypertension (APH) can become a trigger of liver regeneration as shear stress following PHx in a rat model. Portal pressures became elevated immediately after 70% and 90% PHx, peaking on postoperative day (POD) 3, and thereafter decreasing in proportion to the diminution of liver regeneration. The portal pressures after 90% PHx were significantly higher than those after 70% PHx even on POD 7, while those of the portocaval (PC) shunt groups decreased following PC shunting both with and without 70% PHx. The liver/body weight (LW/BW) ratio also decreased in the PC shunt both with and even without 70% PHx. The gradient expressions of class I antigen on sinusoidal endothelial cells (SEC) were found only in the periportal area, which has the highest portal pressure in the healthy rat liver. However, after hepatectomy these expressions were detected from the periportal area to the central venous area. These results suggest that APH as shear stress following PHx may not only become a trigger of hepatocyte regeneration, but also of SEC regeneration, and that surplus APH induces liver dysfunction.

Animals↗
PubMed1994

Rapid activation of post-hepatectomy factor/nuclear factor kappa B in hepatocytes, a primary response in the regenerating liver.

The liver represents one of the few organs in the intact animal that has the capacity to regenerate following injury or partial hepatectomy. One of the earliest responses that has been detected in the remnant liver is the activation of post-hepatectomy factor(s) (PHF), a kappa B site DNA binding activity. We reasoned that understanding the molecular nature of PHF might provide insight into what triggers liver regeneration. We found that PHF is rapidly activated and turned over in the regenerating liver, demonstrating peak activity at 30 min post-hepatectomy and virtual disappearance by 1 h. As determined by supershift, cross-linking, and cross-linking/immunoprecipitation analyses, PHF contains intact p50/p65nuclear factor kappa B (NF-kappa B) subunits. To explore the basis for activation of PHF/NF-kappa B in the regenerating liver, we determined the level of individual Rel family subunits in the nuclei of normal and regenerating liver cells. We found evidence for nuclear translocation of p65/RelA, but other Rel family proteins including p50/NF-kappa B1 and p52/NF-kappa B2 are present at a low level in the nuclei of cells at a constitutive level pre- and post-hepatectomy and appear not to form DNA binding homodimers. The level of I kappa B-alpha falls slightly then increases at 3 h post-hepatectomy in concert with the induction of its mRNA. As demonstrated by the induction of I kappa B-alpha mRNA in hepatocytes in situ and identification of PHF/NF-kappa B in cultured hepatocytes, PHF/NF-kappa B is localized primarily in hepatocytes in the regenerating liver. This represents one of the few examples of NF-kappa B activation in the intact animal in a non-hematopoietic cell type. The activation of PHF/NF-kappa B suggests a mechanism by which hepatocytes regulate their mitogenic program during liver regeneration.

Animals↗
PubMed1978

The effect of splanchnic viscera removal upon canine liver regeneration.

The influence of portal blood factors on canine liver regeneration was studied with graded nonhepatic splanchnic evisceration, coupled with 44 and 72 per cent hepatectomies. In one type of experiment, the pancreas was retained while the rest of the intra-abdominal gastrointestinal tract was removed. In a second variety, total pancreatectomy was performed with preservation of the intra-abdominal organs. In a third kind of experiment, total nonhepatic splanchnic evisceration was performed. Liver regeneration after hepatectomy was decreased by all three kinds of viscera removed as judged by deoxyribonucleic acid synthesis, autoradiography and mitotic index. Pancreatectomy and nonpancreatic splanchnic evisceration caused almost equal decreases in the regenerative response. Total nonhepatic splanchnic evisceration essentially halted regeneration during the first three postoperative days and intraportal infusions of insulin or glucagon, or both together, did not reverse this effect. The decrease in liver membrane bound adenyl cyclase activity and biphasic change in liver cyclic 3', 5' -adenosine monophosphate concentrations normally seen after partial hepatectomy were disrupted after the various eviscerations. Adenyl cyclase activity and cyclic 3', 5' -adenosine monophosphate concentrations tended to be higher than normal in the eviscerated dogs. These observations provide more support for our previously proposed hypothesis that control of liver regeneration is by multiple factors. Pancreatic hormones are important modifiers of this response but, by no means, exercise exclusive control. Other substances of gastrointestinal origin, presumably including hormones and nutrient supply apparently play important specific roles. The volume of portal flow is a secondary and nonspecific, but possibly significant, factor.

Adenylyl Cyclases↗
PubMed2002

Changes in ultrastructure and the occurrence of permeability transition in mitochondria during rat liver regeneration.

Mitochondrial bioenergetic impairment has been found in the organelles isolated from rat liver during the prereplicative phase of liver regeneration. To gain insight into the mechanism underlying this impairment, we investigated mitochondrial ultrastructure and membrane permeability properties in the course of liver regeneration after partial hepatectomy, with special interest to the role played by Ca2+ in this process. The results show that during the first day after partial hepatectomy, significant changes in the ultrastructure of mitochondria in situ occur. Mitochondrial swelling and release from mitochondria of both glutamate dehydrogenase and aspartate aminotransferase isoenzymes with an increase in the mitochondrial Ca2+ content were also observed. Cyclosporin-A proved to be able to prevent the changes in mitochondrial membrane permeability properties. At 24 h after partial hepatectomy, despite alteration in mitochondrial membrane permeability properties, no release of cytochrome c was found. The ultrastructure of mitochondria, the membrane permeability properties and the Ca2+ content returned to normal values during the replicative phase of liver regeneration. These results suggest that, during the prereplicative phase of liver regeneration, the changes in mitochondrial ultrastructure observed in liver specimens were correlated with Ca2+-induced permeability transition in mitochondria.

Animals↗
PubMed1993

Regulation of liver regeneration by interleukin-2 and its inhibitors: cyclosporine A and FK 506.

Several investigations have been suggesting that lymphocytes can be responsible for growth regulation of liver. The interleukin-2 (IL-2) production by spleen cells was noted to be increased 2 days after resection of 70% of the volume of the liver in C3H/He mice. The effects of IL-2 production and its antagonists: cyclosporine A (CsA) and FK506 on liver regeneration were thus studied by measuring in vivo incorporation of Bromodeoxyuridine (BrdU). By intraperitoneal injection of IL-2 5 times every 8 h after hepatectomy. BrdU labeling indices at 36 h after the operation were suppressed in a dose-dependent manner. On the other hand, treatment with CsA and FK506, which inhibit IL-2 production, increased the mitotic indices of the regenerating livers. Serum levels of aminotransferases were not affected by FK506 at a dose sufficient for the mitotic stimulation. Based on these results, CsA and FK506 would appear to stimulate liver cell proliferation by suppressing IL-2 production and inhibiting of NK cell activity.

Animals↗
PubMed1980

[Some features of nuclear genome transcription at early stages of liver regeneration. Nuclear DNA-like RNAs, complementary to uniquie and repeating sequences of DNA].

Transcription of unique and repeating sequences of DNA at early stages of liver regeneration after partial hepatectomy was studied. The total nuclear dRNA (tdRNA) and its two fractions (dRNA63O and dRNA85O) from the control and regenerating liver were subjected to hybridization with the excess of DNA. One hour after partial hepatectomy the kinetics of tdRNA hybridization did not differ from the controls; 3 hrs after operation the rate of unique transcripts hybridization was decreased. The rate of dRNA63O hybridization was shown to be considerably decreased 3 hrs after partial hepatectomy, while the kinetics of hybridization of dRNA85O remained unchanged. It was assumed that the changes of dRNA hybridization during the first few hours after partial hepatectomy are due to a significant increase in the amount of copies of some unique transcripts.

Animals↗
PubMed1980

Thyroxine 5'-monodeiodinase activity in regenerating liver of triiodothyronine-treated rats.

The effect of triiodothyronine (T3) on hepatic thyroxine (T4) 5'-monodeiodinase and the subcellular localization of the enzyme were examined in regenerating rat liver, because it seemed likely that the effect of T3 might be accentuated during liver regeneration. Five days after T3 treatment, the specific activity of the monodeiodinase in the microsomal fraction (105,000 X g pellet) of regenerating liver was increased to 207% of the control value. Lineweaver-Burk plots showed that the Vmax for T4 5'-monodeiodination was about 3 times greater in T3-treated rats than in controls, but that there was no difference between the two groups in the apparent Km value for T4. About 55% of the total enzyme activity was found in the endoplasmic reticulum (ER) of the liver of both controls and T3-treated rats. The subcellular distribution of the enzyme was similar to that of NADPH-cytochrome c reductase (NADPH-cyt c reductase), a marker of the ER, but different from that of Na+,K+-ATPase, a marker of plasma membranes (PM).

Animals↗
PubMed1993

Prostaglandin E2 and rat liver regeneration.

BACKGROUND: Prostaglandin (PG) is reported to be involved in hepatic regeneration. However, little is known about the detailed relation in PG-induced stimulation of the proliferation. The present study was attempted to elucidate the relation. METHODS: The serial change of PGE2 level released from the regenerating rat liver and the effect of PGE2 on the proliferation of rat hepatocytes were studied, with special reference to PGE2 binding and cyclic AMP (cAMP). RESULTS: The PGE2 level increased 3 hours and 10 hours after partial hepatectomy. Timings of these increases seemed to coincide with those of the first and second increase of cAMP in the liver before the initiation of DNA synthesis. DNA synthesis of hepatocytes in primary culture between 24 and 36 hours, 36 and 48 hours, and 48 and 60 hours of culture were significantly enhanced by addition of PGE2 between 4 and 24 hours of culture at concentrations of 2 nmol/L to 1 mumol/L, 2 nmol/L to 200 nmol/L, and 5 mumol/L to 10 mumol/L, and 2 nmol/L and 10 mumol/L, respectively. Enhancement of DNA synthesis with PGE2 at concentrations less than 1 mumol/L seemed to be associated with the high-affinity binding and that at high concentrations with the low-affinity binding. Intracellular cAMP level in the hepatocytes increased during culture, and its increase was enhanced by PGE2 addition. CONCLUSIONS: It is suggested that PGE2 production in the liver increases biphasically during hepatic regeneration and that PGE2 enhances the proliferation of hepatocytes by a specific receptor-mediated process, which is largely associated with cAMP-dependent process.

Animals↗
PubMed2004

[Liver regeneration after hepatectomy].

It is well known that the normal liver has enormous regenerative capacity. Despite years of effort by numerous investigators, there is still uncertainty about the signals of liver regeneration. Computed tomography (CT) is the most useful tool because it accurately measures human liver volume. Comparing the differences in regeneration after major resection of normal and injured livers, normal livers reached plateau levels within 1 to 2 months regardless of the extent of resection, whereas regeneration was retarded in injured liver. Human liver regeneration is influenced by the extent of resection. In biliary cancer, liver regeneration terminates when the liver has regained about three-quarters of its original size in about 1 year. The clinical significance of the observation that liver regeneration is an incomplete process is unclear. However, the strong correlation observed between body surface area and regenerated liver volume suggests that liver regeneration is a process of restoration of the liver to a volume suitable for body size. In living related-donor liver transplantation there is a tendency for the size of the transplanted liver to converge to the standard liver volume, regardless of whether the initial liver-graft volume was smaller or larger than the standard liver volume.

Animals↗
PubMed1989

Impaired liver regeneration in the analbuminemic rat.

Albumin has been implicated as both an inhibitor and a stimulator of liver regeneration. We examined the rate of liver regeneration following partial hepatectomy in rats which are genetically analbuminemic. Adult male analbuminemic and Sprague-Dawley control rats underwent either a 70% partial hepatectomy or a sham operation. Twenty-four hours postoperatively, rats were injected iv with tritiated thymidine and the liver remnants were resected 1 hr later. Liver weight, protein and DNA contents, and the rate of tritiated thymidine incorporation into DNA were determined. The rate of DNA synthesis in control sham-operated rats was greater (P less than 0.05) than that of analbuminemic rats. Following partial hepatectomy, there was a statistically significant (P less than 0.01) increase in DNA synthesis in control rats; no significant increase was noted in the analbuminemic rats. No significant differences in liver remnant weight or protein and DNA contents were noted between control and analbuminemic sham-operated or partially hepatectomized rats. Our data suggest that albumin plays a role in the regulation of DNA synthesis in both the resting and the regenerating liver and it may be essential in maintaining a normal rate of liver regeneration.

Albumins↗
PubMed2005

Beneficial effect of hyperbaric oxygenation on liver regeneration in cirrhosis.

BACKGROUND: Underlying hepatic injury and cirrhosis are leading factors that interfere with the post-operative liver regeneration and function. Hyperbaric oxygenation (HBO) has been reported to ameliorate the ischemia-reperfusion injury of the liver, to induce compensatory hypertrophy of the predicted remnant liver in rats after portal vein ligation and to augment liver regeneration after hepatectomy in non-cirrhotic rats. Our aim was to determine the effect of HBO treatment on liver regeneration after partial hepatectomy in normal and cirrhotic mice in this experimental study. MATERIALS AND METHODS: The effect of HBO on liver regeneration was studied in a mice model combining carbon tetrachloride induced cirrhosis and partial hepatectomy. Mice were divided into four groups: Control, cirrhotic, non-cirrhotic HBO-treated, and cirrhotic HBO-treated. All animals underwent 40% hepatectomy. Liver regeneration was evaluated by the proliferating cell nuclear antigen-labeling index. Serum aspartate aminotransferase and alanine aminotransferase levels were measured to evaluate liver injury. RESULTS: Serum alanine aminotransferase and aspartate aminotransferase levels were significantly decreased in HBO-treated cirrhotic group compared to cirrhosis group after hepatectomy (P = 0.001 and P = 0.014, respectively). The proliferating cell nuclear antigen labeling index was significantly higher in HBO treated cirrhotic group than in cirrhotic group after hepatectomy (P = 0.022). CONCLUSIONS: Our results suggest that HBO treatment improves liver functions and augments hepatocyte regeneration in cirrhotic mice after hepatectomy. Post-operative HBO treatment may have a beneficial effect on post-operative liver function and regeneration in cirrhotic patients.

Alanine Transaminase↗
PubMed2006

Expression patterns and action analysis of genes associated with drug-induced liver diseases during rat liver regeneration.

AIM: To study the action of the genes associated with drug-induced liver diseases at the gene transcriptional level during liver regeneration (LR) in rats. METHODS: The genes associated with drug-induced liver diseases were obtained by collecting the data from databases and literature, and the gene expression changes in the regenerating liver were checked by the Rat Genome 230 2.0 array. RESULTS: The initial and total expression numbers of genes occurring in phases of 0.5-4 h after partial hepatectomy (PH), 4-6 h after PH (G0/G1 transition), 6-66 h after PH (cell proliferation), 66-168 h after PH (cell differentiation and structure-function reconstruction) were 21, 3, 9, 2 and 21, 9, 19, 18, respectively. It is illustrated that the associated genes were mainly triggered at the initial stage of LR and worked at different phases. According to their expression similarity, these genes were classified into 5 types: only up-regulated (12 genes), predominantly up-regulated (4 genes), only down-regulated (11 genes), predominantly down-regulated (3 genes), and approximately up-/down-regulated (2 genes). The total times of their up- and down-expression were 130 and 79, respectively, demonstrating that expression of most of the genes was increased during LR, while a few decreased. The cell physiological and biochemical activities during LR were staggered according to the time relevance and were diverse and complicated in gene expression patterns. CONCLUSION: Drug metabolic capacity in regenerating liver was enhanced. Thirty-two genes play important roles during liver regeneration in rats.

Animals↗
PubMed2005

Adenovirus-mediated overexpression of the activin betaC subunit accelerates liver regeneration in partially hepatectomized rats.

BACKGROUND/AIMS: The expression level of the activin betaC subunit is high in normal liver and reduces after partial hepatectomy, but its function is controversial. METHODS: To determine the role of the betaC subunit during liver regeneration, we overexpressed the betaC subunit gene in the liver by infusing adenovirus vector encoding the flag-tagged betaC subunit into the portal vein. Adenovirus vector encoding the beta-galactosidase was also infused as a control. Seventy percent hepatectomy was performed 4 days after the infection. RESULTS: Approximately 20% of hepatocytes expressed the flag-tagged betaC subunit at the time of hepatectomy and approximately 50% of hepatocytes expressed the betaC subunit 3 days after hepatectomy. In betaC-infected liver, bromodeoxyuridine labeling was significantly greater at 24 and 48 h after partial hepatectomy compared with the control liver. Consistent with this observation, the liver regeneration rate was significantly greater in betaC-transfected liver at 72 and 96 h after hepatectomy. Many of the bromodeoxyuridine-positive nuclei were observed in or by the betaC-transfected hepatocytes. CONCLUSIONS: These results indicate that liver regeneration is accelerated in betaC-overexpressing liver. The betaC subunit may function to promote replication of hepatocytes during liver regeneration.

Adenoviridae↗