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PubMed1987

The effects of postoperative factors on serum thyroid hormones and rat liver nuclear 3,5,3'-triiodothyronine receptor concentrations in surgical models of uremia and regenerating liver.

We have determined the individual effects of postoperative fasting, surgical/anesthetic factors, acute uremia (AU), and regenerating liver (RL) on nucleoplasmic (NP; 0.15 M KCl-extractable) and chromatin-bound (CB; 0.4 M KCl-extractable) rat liver T3 receptors. AU and RL rats were studied 24 h after bilateral nephrectomy (blood urea nitrogen, 128 +/- 13 mg/dl) or two thirds hepatectomy, respectively. The effects of postoperative fasting were assessed by comparison of normal rats (N) with control rats (N6) pair-fed to match the caloric intake of the AU and RL rats. Surgical/anesthetic effects were determined by comparison of N6 rats with sham-operated pair-fed rats (S6). The effects of AU or RL were obtained by comparison with S6 controls. Changes in mean body weight attributable to fasting (N6-N), surgical/anesthetic effects (S6-N6), acute uremia (AU-S6), and regenerating liver (RL-S6) were: -17.3 (P less than 0.001), -4.0 (P = NS), -4.5 (P less than 0.05), and -1.0 g/24 h (P = NS), respectively. Changes in mean serum T4 (N, 5.3 +/- 1.3 micrograms/dl) were: -1.0 (P = NS), -0.6 (P = NS), -0.9 (P less than 0.05), and -1.0 micrograms/dl (P less than 0.05), respectively. Changes in mean serum T3 (N, 53 +/- 23 ng/dl) were: -8 (P = NS), -18 (P less than 0.05), -10 (P = NS), and -14 ng/dl (P less than 0.05), respectively. The NP and CB receptor pools of the AU and RL rats were not significantly different from those of age-matched N rats (NP, 25 +/- 5 fmol/mg DNA; CB, 405 +/- 134 fmol/mg DNA). Chronically uremic (CU) rats 2 weeks after five sixths nephrectomy (blood urea nitrogen, 36 +/- 2 mg/dl) did not exhibit significant change in their extractable receptor pools. Complete starvation for 24 h (NO) or 72 h (NOO) generally resulted in marked reductions in receptor concentrations compared to those in age-matched N rats fed ad libitum: NP pool (N, 31 +/- 17 fmol/mg DNA): NO-N, -40% (P = NS); NOO-N, -59% (P less than 0.01); CB pool (N, 303 +/- 105 fmol/mg DNA): NO-N, -19% (P less than 0.05); NOO-N, -41% (P less than 0.001). These studies indicate that severe AU, moderate CU, and LR have relatively little effect on solubilized rat liver nuclear receptor concentrations. In contrast, complete starvation is a potent depressant of both nuclear receptor pools. In the surgical models of AU and LR, postoperative fasting was the primary cause of weight loss.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

[Hepatic protein synthesis in regenerating liver after partial hepatectomy].

The process of hepatic protein synthesis was studied in the regenerating liver after partial hepatectomy (HTX). Hepatocellular protein synthesis (HPS) and secretory protein synthesis (SPS) were determined in the regenerating liver of rats after 68% HTX. The serum levels of the following items were determined in 10 patients before and after HTX: interleukin-6 (IL-6), acute-phase proteins (APP), and negative acute-phase proteins (NAPP). HPS has markedly increased after HTX, with the peak occurring at 48 hours. The regenerating rat liver showed an increase of 80% over normal livers in HPS and 200% in SPS 48 hours after HTX. A remarkable increase in IL-6 levels occurred on the first day after HTX. In all patients transient falls in APP levels occurred on the first day. Values appeared to return rapidly toward preoperative values by 3 or 5 days after HTX but failed to show any significant increase compared to preoperative values. In contrast to APP, prolonged decreases in NAPP levels occurred after HTX. Values declined to a nadir on the first or third day after HTX and remained suppressed for 14 days. These results suggest that the production of APP is activated at an early stage of liver regeneration after partial hepatectomy.

Acute-Phase Proteins↗
PubMed1981

[Study of the biological activity of chalones isolated from normal and regenerating liver].

In contrast to the extract derived from the normal rat liver, the chalone-containing extract from the regenerating liver did not inhibit hepatocyte division in the in-vivo test system 22 hours or 28 days after partial hepatectomy. The regenerating liver extract reduced by 55% the level of DNA synthesis by hepatocytes 28 days after hepatectomy. The testing of biological activity of individual protein fractions of the chalone-containing extract from the regenerating rat liver which were separated by preparative slab gel electrophoresis revealed (28 days after hepatectomy) the coexistence in the extract of both stimulant of hepatocyte mitosis and inhibitor of DNA synthesis. It is assumed that the lack of the inhibitory effect in the chalone-containing extracts from the regenerating liver might be related to the competitive interconnections between the inhibitors and stimulants of mitosis rather than to the loss of the tissue-specific inhibitor.

Animals↗
PubMed1987

[Experimental study of the effect of an elemental diet on liver regeneration].

The influence of branched chain amino acids and lipid on liver regeneration was examined after two-thirds hepatectomy in rats. Elemental diet (ED) as components of enteral nutrition was given through the gastrostomy tube. The rats were divided into four groups according to the amounts of branched chain amino acids (BCAA) and lipid in the diet as follows: ED-I; BCAA 27%, Cal/N ratio: 74, ED-II; BCAA 37%, Cal/N ratio: 95, ED-III; BCAA 37% + lipid emulsion, Cal/N ratio: 99, ED-AC; commercially available elemental diet. The degree of liver regeneration of these groups of rats were compared with that of the control rats which were fed per os ad libitum. The liver regeneration rate of each group was as follows: ED-I; 59%, ED-II; 88%, ED-III; 92%, ED-AC; 79%, the control group; 89%. Remarkable fatty deposits were microscopically observed in each liver of ED-I, II and AC groups. Fatty change in the liver of ED-III group was minimum. The observation indicates that administration of branched chain amino acid enriched elemental diet and lipid emulsion is effective for regeneration of the liver after partial hepatectomy.

Amino Acids, Branched-Chain↗
PubMed1997

Initiation of liver growth by tumor necrosis factor: deficient liver regeneration in mice lacking type I tumor necrosis factor receptor.

The mechanisms that initiate liver regeneration after resection of liver tissue are not known. To determine whether cytokines are involved in the initiation of liver growth, we studied the regeneration of the liver after partial hepatectomy (PH) in mice lacking type I tumor necrosis factor receptor (TNFR-I). DNA synthesis after PH was severely impaired in these animals, and the expected increases in the binding of the NF-kappaB and STAT3 transcription factors shortly after PH failed to occur. Binding of AP-1 after PH was decreased in TNFR-I knockout mice compared with animals with the intact receptor whereas C/EBP binding was not modified. Injection of interleukin 6 in TNFR-I-deficient animals 30 min before PH corrected the defect in DNA synthesis and restored STAT3 and AP-1 binding to normal levels but had no effect on NF-kappaB binding in the regenerating liver. The results indicate that TNF, signaling through the TNFR-I, can initiate liver regeneration and acts by activating an interleukin 6-dependent pathway that involves the STAT3 transcription factor.

Animals↗
PubMed1989

Effect of glucocorticoid on liver regeneration after partial hepatectomy in the rat.

The increase in activities of hepatic thymidylate synthetase (EC 2.1.1.45) and thymidine kinase (EC 2.7.1.21), which catalyse the formation of thymidylate through the de novo and salvage pathways, respectively, were significantly suppressed during liver regeneration in rats which were given glucocorticoids (hydrocortisone and dexamethasone) or indomethacin. These drugs also prevented the augment of hepatic DNA content in 24 h regenerating liver.

Animals↗
PubMed1996

C/EBP-beta/LAP controls down-regulation of albumin gene transcription during liver regeneration.

Expression of the albumin gene in the liver is controlled by several liver-enriched transcription factors. However, the mechanisms which contribute to its regulation during pathophysiological states, such as liver regeneration, are still little understood. In the present study we found that during liver regeneration down-regulation of albumin mRNA expression is transcriptionally controlled through a minimal element (nucleotide -170 to +22) of the albumin promoter and is observed mainly during the G1 phase of the cell cycle, while high levels of albumin expression are preserved at later time points. Decreased albumin mRNA levels correlate with a dramatic increase in nuclear expression of C/EBP-beta/LAP, a protein known to bind to the D site of the albumin promoter and also to be involved in cell cycle control. In contrast, nuclear expression of other factors such as HNF-1 or C/EBP-alpha, which also have been shown to transcriptionally control albumin expression, is either unchanged or slightly decreased. We show that pre- and post-translational mechanisms are involved in the higher nuclear expression of C/EBP-beta/LAP as early as 1 h after hepatectomy, which also leads to its increased binding toward the D site of the albumin promoter. Finally, in vitro transcription assays with liver nuclear extracts and recombinant C/EBP-beta/LAP demonstrate that C/EBP-beta/LAP can directly down-regulate transcription mediated by the minimal element of the albumin promoter. Additionally the inhibitory role of C/EBP-beta/LAP on the albumin minimal promoter could be confirmed by transfection experiments in hepatoma cells. These results indicate that C/EBP-beta/LAP, while enhancing transcription of cell cycle-related genes and controlling G1/S phase checkpoint, down-regulates a major liver function, i.e. albumin synthesis, to prepare the hepatocyte for entry into the cell cycle.

Albumins↗
PubMed1995

Gene expression of N-acetylglucosaminyltransferases III and V: a possible implication for liver regeneration.

N-acetylglucosaminyltransferases III and V (GnT-III and -V) are key enzymes in the synthesis of the branches of asparagine-linked oligosaccharides. Although their messenger RNAs (mRNAs) are expressed in various rat tissues, they are not detected in normal rat liver. Expression of the GnT-III and -V mRNAs, however, increased in regenerating liver after two-thirds partial hepatectomy compared with sham-operated rats. The enzymatic activities of GnT-III and -V increased in proportion to mRNA expression. To determine which type of cells in the liver have high activities of these glycosyltransferases, hepatocytes and nonparenchymal cells were separated by means of a two-step collagenase perfusion technique. GnT-III activity was only detected in nonparenchymal cells of normal rat liver. However, during liver regeneration, GnT-III activity increased and thus was also detectable in hepatocytes. GnT-V activity was detected in both types of cells. These data were supported by reverse transcription-polymerase chain reaction results. Although the mechanism underlying the induction of these glycosyltransferases is unknown, lectin blot analysis showed that oligosaccharides in many glycoproteins, including hepatocyte growth factor, a major growth factor associated with liver regeneration, were newly synthesized during liver regeneration. This is the first report on the expression of glycosyltransferases during liver regeneration and suggests that there are different mechanisms involved in regulation of the genes of GnT-III and -V during liver regeneration.

Animals↗
PubMed1976

Role of the hypophysis in estrogen-mediated induction of enzymes in the regenerating liver from castrated male rats.

Perfusions with corticosterone, of isolated regenerated livers from adult male rats, subjected to castration, partial hepatectomy and hypophysectomy with or without estradiol treatment during parenchymal regeneration, yielded very similar patterns of biliary steroid metabolites. The degree of steroid conjugation was lower than that seen in livers from normal, untreated, adult male rats. In operated animals, with or without estradiol benzoate treatment, ring A-reduced 20-keto metabolites constituted about 20%, whereas metabolites with a 20-hydroxy group made up approximately 80% of the corticosterone metabolites formed. Furthermore, no 15-hydroxylated metabolites derived from corticosterone, quantitatively the most important compounds in bile from female rats, could be detected in bile from these treated male animals. However, livers from male rats which had been castrated, hepatectomized and treated with estradiol benzoate during liver regeneration, produced 15-hydroxy-tetrahydrocorticosterone to the same extent as female rat livers, when perfused with corticosterone. The results obtained indicate that the effects of estradiol on the induction and differentiation of steroid metabolizing enzymes in the regenerating liver are pronounced and manifested only in the presence of an intact hypophysis.

Animals↗
PubMed1976

[The activity of polynucleotide phosphorylase in polyribosomes of regenerating liver of adult rats, liver of newborn rats and in some reinoculated tumours].

Specific activity and level of polynucleotide phosphorylase (PNPase) in polyribosomes of regenerating liver of adult rats, liver of newborn rats and in malignant tumours of rat (sarcoma M-1 and hepatoma 27) were studied. 24 hours after partial hepatectomy the specific activity and level of PNPase in regenerating liver decreased 3--4 times in the fraction of polyribosomes, bound to the endoplasmic reticulum membranes, and remained at a constantly low level in the fraction of free polyribosomes. The PNPase activity also showed a sharp decrease in the fraction of membrane-bound polyribosomes from newborn rats liver and could not be detected either in free or in bound polyribosomes from sarcoma M-1 or hepatoma 27. The PNPase activity in the fraction of bound polyribosomes increased with a decrease in the rate of liver growth (regenerating liver and newborn rats liver), and reached the level normal for adult animals. Possible mechanisms of regulation of the PNPase activity in animal tissue were studied. It was found that a 2-fold administration of cyclic 3,5'-AMP to intact animals (5 mg per 100 g of body weight) with an interval of 8 hours, corresponding to the interval between two peaks of the increase in cyclic 3,5'-AMP concentration following partial hepatectomy, diminished the PNPase specific activity in polyribosomes by 30%. A factor, presumably of protein origin, which induced a release of PNPase from polyribosomes of normal rat liver but did not affect the activity of the liberated enzyme, was detected in the cell sap of sarcoma M-1 and hepatoma 27.

Age Factors↗
PubMed1959

Effect of thioacetamide on rat liver regeneration. II. Nuclear RNA in mitosis.

The effect of thioacetamide on dividing cells of regenerating rat liver has been studied. Rats were given daily subcutaneous injections of thioacetamide as a 1 per cent solution at a dosage of 5 mg./100 gm. body weight for 7 to 10 days, subjected to partial hepatectomy, and sacrificed 28 to 31 hours later. Thioacetamide treatment results in striking increases in the nuclear ribonucleoproteins of the liver cell without affecting the mitotic rate during regeneration (14). During mitosis, RNA-containing particles were seen within the spindle and coating the contracted chromosomes from prophase through metaphase or early anaphase. At telophase, prior to the reconstruction of the nuclear membrane, fine RNA-containing granules appeared within the compact chromosomal groups. These coalesced to form nucleoli corresponding in number to the number of nucleolar organizer regions. The nuclei and nucleoli showed a rapid increase in size during the reconstruction period when compared with corresponding figures of the control liver samples. Electron micrographs of interphase nucleoli indicated a similar basic granular structure in both drug-treated and control animals. The question is raised as to whether the increased nucleolar material merely made visible some of the nucleolar-chromosomal associations that normally occur in mitosis, or whether thioacetamide directly affects the synthetic activity of the contracted mitotic chromosomes.

Amides↗
PubMed2003

Protection against liver damage by cardiotrophin-1: a hepatocyte survival factor up-regulated in the regenerating liver in rats.

BACKGROUND & AIMS: Cardiotrophin-1 (CT-1) is a member of the interleukin 6 (IL-6) family of cytokines, which protect cardiac myocytes against thermal and ischemic insults. In this study, we investigated the expression of CT-1 by liver cells and its possible hepatoprotective properties. METHODS: We analyzed the production, signaling, and antiapoptotic properties of CT-1 in hepatocytes and the expression of this cytokine during liver regeneration. We also investigated whether CT-1 might exert protective effects in animal models of liver damage. RESULTS: We found that CT-1 is up-regulated during liver regeneration and exerts potent antiapoptotic effects on hepatocytic cells. Hepatocytes cultured under serum starvation or stimulated with the pro-apoptotic cytokine transforming growth factor beta (TGF-beta) produce CT-1, which behaves as an autocrine/paracrine survival factor. Treatment with an adenovirus encoding CT-1 efficiently protects rats against fulminant liver failure after subtotal hepatectomy, an intervention that causes 91% mortality in control animals whereas 54% of those receiving CT-1 gene therapy were long-term survivors. This protective effect was associated with reduced caspase-3 activity and activation of the antiapoptotic signaling cascades signal transducer and activator of transcription (Stat-3), extracellular regulated kinases (Erk) 1/2, and Akt in the remnant liver. Gene transfer of CT-1 to the liver also abrogated Concanavalin A (Con-A) liver injury and activated antiapoptotic pathways in the hepatic tissue. Similar protection was obtained by treating the animals with 5 microg of recombinant CT-1 given intravenously before Con-A administration. CONCLUSIONS: We show that CT-1 is a hepatocyte survival factor that efficiently reduces hepatocellular damage in animal models of acute liver injury. Our data point to CT-1 as a new promising hepatoprotective therapy.

Adenoviridae↗
PubMed2004

[Liver regeneration after resection: molecular and cellular mechanism].

It has been well established that the liver can regenerate after resection. Liver regeneration is a fundamental mechanism by which the liver responds to injury. This review article discusses molecular and cellular mechanism of liver regeneration, including growth factors and cytokines in the initiation and regulation of liver regeneration, the importance of the liver extracellular matrix and its dynamic effect on hepatocyte growth, and finally, stem cell biology in liver regeneration.

Animals↗
PubMed1996

Influence of continuous interleukin-2 administration via the portal vein on liver regeneration following partial hepatectomy in rats.

We have reported the efficacy of intraarterial-combined immunochemotherapy including interleukin-2 (IL-2) for unresectable hepatocellular carcinoma (HCC). To further test this therapy for prevention of intrahepatic recurrence after hepatectomy, the influence of IL-2 on liver regeneration was examined using mitotic index (MI) and the bromodeoxyuridine (BrdU) labeling index (LI) in 70% hepatectomized Donryu rats. In addition, gap junction appearance, which may change during liver regeneration, was analyzed using a monoclonal antibody (HAM8). Serum albumin, alanine transaminase, and total bilirubin (TB) levels were also evaluated. IL-2 (45,000 Japanese reference units [JRU]/d) or saline was administered continuously via the portal vein immediately after hepatectomy using an infusion pump. We also examined the influence of IL-2 on liver regeneration after hepatectomy with splenectomy. No difference in the weight of the liver, serum albumin, alanine transaminase, or TB was observed in any groups at 1, 2, or 4 days after hepatectomy. Neither IL-2 nor splenectomy influenced MI and BrdU LI at all three points. Gap junctions began to disappear after hepatectomy and reached a minimum on day 2 in all groups. Four days after hepatectomy, the density of the reappearing gap junctions was markedly lower in groups treated with IL-2 than in those receiving saline with or without splenectomy. However, the density returned to close to preoperative levels 6 days after hepatectomy in all groups. Continuous portal infusion of IL-2 transiently disturbed gap junction reappearance during liver regeneration. However, no other parameters of liver regeneration or liver functions differed. These results suggest that the liver regeneration after partial hepatectomy may be suppressed by the administration of IL-2, even though the suppression may not be harmful for overall recovery of the resected liver. However, it seems that hepatic IL-2 administration can be performed without serious complications after hepatectomy.

Alanine Transaminase↗
PubMed2006

Conditional deletion of c-myc does not impair liver regeneration.

The oncogene c-myc encodes a transcription factor that has long been considered essential to liver regeneration, the process by which fully differentiated hepatocytes proliferate in an attempt to maintain a normal functional mass in response to hepatic injury. Experimental liver regeneration can be induced upon 70% partial hepatectomy and is accompanied by an increase in c-myc expression accompanying the synchronous entry of remaining hepatocytes into the cell cycle. Because liver regeneration is an essential process for achieving liver homeostasis, therapies directed at reducing MYC expression in hepatocellular carcinoma are fraught with the theoretical possibility of injuring adjacent noncancerous liver cells, thereby restricting the liver's normal regenerative response to injury. To determine if intact c-myc is required for liver regeneration, we reduced hepatic c-myc in c-myc(fl/fl) mice using an adenoviral vector that expresses Cre recombinase. Despite a 90% decrease in hepatic expression of c-myc, restoration of liver mass 7 days later was not compromised. Reconstituted liver retained the same decrease in hepatic c-myc, indicating that hepatocytes deficient in c-myc were able to proliferate in response to partial hepatectomy. Although c-myc is required for embryonic development, our findings indicate that it is not required for the maintenance of the adult liver.

Alleles↗
PubMed1997

Liver regeneration attenuates increased voluntary alcohol intake evoked by the liver damage.

Liver dysfunction induced in Wistar rats either surgically (by construction of portocaval anastomosis) or chemically (by chronic administration of thioacetamide) led to increased voluntary alcohol intake. Alcohol preference could be attenuated by liver regeneration that was triggered by a two-thirds hepatectomy done on cirrhotic rats. The brain serotonin system was activated in portocaval anastomosis rats and unchanged in thioacetamide-treated rats, thus suggesting that serotonin is not likely to be implicated in the mechanism(s) underlying development of alcohol preference in these rats. Also, tetrahydro-beta-carboline could possibly be excluded from consideration. Neither change in the brain concentration or distribution of tetrahydrobetacarboline after long-term treatment with thioacetamide could be found.

Alcohol Drinking↗
PubMed1993

Regulation of hepatic and non-hepatic apolipoprotein A-I and E gene expression during liver regeneration.

In this study, we have determined what tissues other than liver express apolipoprotein (apo) A-I and apo E genes during liver regeneration at the level of the specific mRNAs, and have compared these findings with the serum values of high-density lipoprotein (HDL), low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL). Our results show that liver and intestine express most of the apo A-I mRNA during liver regeneration. Although apo E mRNA is expressed principally by the liver, its expression is reduced in liver during regeneration but is increased markedly in non-hepatic tissues, such as in intestine, kidney, lung and brain. These results suggest that humoral or circulating factors released during liver regeneration influence apolipoprotein E gene expression, not only in hepatic but also in non-hepatic tissue.

Animals↗
PubMedDate not supplied

The effect of hepatic stimulator substance (HSS) on liver regeneration arrest induced by 5-HT2 receptor blockade.

BACKGROUND: The restorative effect of hepatic stimulator substance (HSS) against hepatic regeneration arrest induced by 5-HT2 receptor blockade was investigated. MATERIALS AND METHODS: Male Wistar rats were subjected to 60-70% partial hepatectomy and to 5-HT2 receptor blockade at 16 h after partial hepatectomy by ketanserin administration (6 mg/kg bodyweight intraperitoneally; group I). HSS at the dose of 100 mg protein/kg bodyweight was administered at 10 or 17 h after partial hepatectomy in ketanserin-treated rats (groups II and III). The mitotic index in hematoxylin-eosin-stained liver sections, immunochemical detection of PCNA and Ki 67 nuclear antigens and the rate of [3H]-thymidine incorporation into hepatic DNA were used as indices of liver regeneration. RESULTS: Liver regeneration, as evaluated by [3H]-thymidine incorporation into hepatic DNA, mitotic index, PCNA and Ki67 nuclear antigens, peaked at 40 h in groups I, II and III of rats and no significant differences were observed between the studied groups. CONCLUSION: HSS administration is not capable of reversing the liver regeneration arrest induced by 5-HT2 receptor blockade.

Animals↗