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PubMed1986

Hepatic glucose-6-phosphate dehydrogenase, cholesterogenesis, and serum lipoproteins in liver regeneration after partial hepatectomy.

Liver regeneration after partial hepatectomy was used as an experimental model for studying mammalian cell division and replication. The rate of cell proliferation in this hyperplastic model was correlated with hepatic de novo synthesis of cholesterol, with the hexose monophosphate shunt pathway of glucose metabolism, and with serum lipoproteins. An increase of hepatic cholesterol esters and of incorporation of tritiated water in cholesterol esters was observed at 24 hr after partial hepatectomy. Partial hepatectomy also resulted in an increase of hepatic glucose-6-phosphate dehydrogenase and in alteration of serum lipoproteins, primarily due to a selective decline in high density lipoprotein fraction.

Cholesterol↗
PubMed2002

Liver regeneration.

Unlike other vital organs, the liver typically regenerates after injury. Indeed, the very factors that cause liver injury initiate a reparative process in the residual liver that includes the induction of cytoprotective mechanisms, deletion of mortally wounded cells, repair of less damaged survivors, liver cell proliferation to replace the cells that died, the deposition of new matrix, and tissue remodeling to restore normal hepatic mass and architecture. During liver regeneration, the liver normally continues to perform vital, liver-specific functions. Unfortunately, the hepatic regenerative response sometimes becomes disrupted--either failing to occur or occurring in a disordered, or incomplete fashion. Abnormal regeneration contributes to the pathogenesis of fulminate liver failure, cirrhosis, and primary liver cancers. Research in the field of regenerative biology has identified several events that are required for liver regeneration. These include injury-induced changes in the hepatic microenvironment, the ability of surviving liver cells and/or their progenitors to proliferate, and a temporary suspension of homeostatic mechanisms that normally couple cell proliferation to programmed cell death. The signals that mediate these complex biologic responses are being detailed. A better understanding of the extra- and intracellular signals that prompt the injured liver to regenerate should suggest treatments to promote liver regeneration in patients with otherwise fatal liver diseases.

Animals↗
PubMed1999

Immediate increase of portal pressure, reflecting sinusoidal shear stress, induced liver regeneration after partial hepatectomy.

The mechanisms whereby hepatocytes in the normal liver can be primed for replication following partial hepatectomy (PHx) are poorly understood. To determine whether "shear stress," which is induced by acute portal hypertension after PHx, is involved in liver regeneration, we studied liver regeneration in rats with splenic transposition (SPT) in which we can minimize the postoperative elevation of portal pressure. Rats underwent 70% PHx following splenic transposition or sham surgery and were killed at various time points to measure portal pressure and other factors. In the control groups, the portal pressure was significantly increased immediately after surgery, peaking at 48 h, and returning to near the preoperative levels by 168 h after PHx. In the SPT group, although portal pressure increased immediately, it decreased to the control levels 6 h after PHx and thereafter repeatedly increased. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels peaked at 24 and 6 h after PHx, respectively. Proliferative cell analysis was done using MIB-5 antibody, and there were no significant differences between the two groups. Furthermore, liver weight was restored in the same way in both groups. Taken together, the results suggest that an immediate increase in portal pressure is necessary for the initiation of liver regeneration.

Animals↗
PubMed2006

Prometheus' challenge: molecular, cellular and systemic aspects of liver regeneration.

The fascinating aspect of the liver is the capacity to regenerate after injury or resection. A variety of genes, cytokines, growth factors, and cells are involved in liver regeneration. The exact mechanism of regeneration and the interaction between cells and cytokines are not fully understood. There seems to exist a sequence of stages that result in liver regeneration, while at the same time inhibitors control the size of the regenerated liver. It has been proven that hepatocyte growth factor, transforming growth factor, epidermal growth factor, tumor necrosis factor-alpha, interleukins -1 and -6 are the main growth and promoter factors secreted after hepatic injury, partial hepatectomy and after a sequence of different and complex reactions to activate transcription factors, mainly nuclear factor kappaB and signal transduction and activator of transcription-3, affects specific genes to promote liver regeneration. Unraveling the complex processes of liver regeneration may provide novel strategies in the management of patients with end-stage liver disease. In particular, inducing liver regeneration should reduce morbidity for the donor and increase faster recovery for the liver transplantation recipient.

Animals↗
PubMed1998

NFkappaB prevents apoptosis and liver dysfunction during liver regeneration.

Although NFkappaB binding activity is induced during liver regeneration after partial hepatectomy, the physiological consequence of this induction is unknown. We have assessed the role of NFkappaB during liver regeneration by delivering to the liver a superrepressor of NFkappaB activity using an adenoviral vector expressing a mutated form of IkappaBalpha. This adenovirus (Ad5IkappaB) was almost exclusively expressed in the liver and inhibited NFkappaB DNA binding activity and transcriptional activity in cultured cells as well as in the liver in vivo. After partial hepatectomy, infection with Ad5IkappaB, but not a control adenovirus (Ad5LacZ), resulted in the induction of massive apoptosis and hepatocytes as demonstrated by histological staining and TUNEL analysis. In addition, infection with Ad5IkappaB but not Ad5LacZ decreased the mitotic index after partial hepatectomy. These two phenomena, increased apoptosis and failure to progress through the cell cycle, were associated with liver dysfunction in animals infected with the Ad5IkappaB but not Ad5LacZ, as demonstrated by elevated serum bilirubin and ammonia levels. Thus, the induction of NFkappaB during liver regeneration after partial hepatectomy appears to be a required event to prevent apoptosis and to allow for normal cell cycle progression.

Adenoviridae↗
PubMed1995

Ornithine decarboxylase induction during liver regeneration in IRS-1-deficient mice.

We investigated the induction of ornithine decarboxylase during liver regeneration after partial hepatectomy in IRS-1-deficient mice. There were no significant differences in ODC activity or the time course of changes in ODC activity between IRS-1-deficient mice and wild-type mice. PI 3'-kinase activity showed similar increases in both groups of mice. Furthermore, ODC induction in IRS-1 transfected CHO cells was studied after stimulation by addition of FCS. The maximal ODC activity was 2.5-fold greater in IRS-1-transfected CHO cells than in control CHO cells. Our results suggest that the IRS-1 pathway may be involved in ODC induction. The absence of a difference in ODC and PI 3'-kinase activity in the regenerating liver between IRS-1-deficient mice and wild-type mice may have been related to the compensatory effects of IRS-2/pp190 [Araki et al. Nature (1994) 372, 186-190; Tobe et al. J.Biol.Chem. (1995) 270, 5698-5701].

Animals↗
PubMed2006

Expression patterns and action analysis of genes associated with physiological responses during rat liver regeneration: Innate immune response.

AIM: To study the relationship between innate immune response and liver regeneration (LR) at transcriptional level. METHODS: Genes associated with innate immunity response were obtained by collecting the data from databases and retrieving articles. Gene expression changes in rat regenerating liver were detected by rat genome 230 2.0 array. RESULTS: A total of 85 genes were found to be associated with LR. The initially and totally expressed number of genes at the phases of initiation [0.5-4 h after partial hepatectomy (PH)], transition from G0 to G1 (4-6 h after PH), cell proliferation (6-66 h after PH), cell differentiation and structure-function reconstruction (66-168 h after PH) was 36, 9, 47, 4 and 36, 26, 78, 50, respectively, illustrating that the associated genes were mainly triggered at the initial phase of LR and worked at different phases. According to their expression similarity, these genes were classified into 5 types: 41 up-regulated, 4 predominantly up-regulated, 26 down-regulated, 6 predominantly down-regulated, and 8 approximately up/down-regulated genes, respectively. The expression of these genes was up-regulated 350 times and down-regulated 129 times respectively, demonstrating that the expression of most genes was enhanced while the expression of a small number of genes was decreased during LR. Their time relevance was classified into 14 groups, showing that the cellular physiological and biochemical activities during LR were staggered. According to the gene expression patterns, they were classified into 28 types, indicating that the cellular physiological and biochemical activities were diverse and complicated during LR. CONCLUSION: Congenital cellular immunity is enhanced mainly in the forepart, prophase and anaphase of LR while congenital molecular immunity is increased dominantly in the forepart and anaphase of LR. A total of 85 genes associated with LR play an important role in innate immunity.

Animals↗
PubMed1985

[Effect of tritoqualine on liver regeneration after partial hepatectomy in rats].

Effect of tritoqualine (TRQ) on liver regeneration after partial hepatectomy in normal rats and chronically injured rats treated with carbon tetrachloride (CCl4) for 12 weeks were investigated by the measurement of serum and liver biochemical parameters concerning the hepatic function. The results are as follows: 1) In normal rats, the liver regeneration rate after partial hepatectomy was increased dose-dependently with the administration of TRQ for 7 days after the operation. TRQ improved BSP retention rate which was decreased after partial hepatectomy. In addition, protein synthetic activity in the liver microsomes prepared from TRQ-administered rats was higher than that prepared from control rats, and the contents of serum total protein, serum albumin and liver protein were also higher in TRQ-administered rats. 2) In the rats treated with CCl4 for 12 weeks, the liver regeneration rate after partial hepatectomy was increased dose-dependently with the administration of TRQ for 6 days. TRQ also improved the contents of serum total protein, serum albumin and liver protein. Though the amount of collagen in the liver chronically injured by CCl4 increased more than twice compared with that in the normal liver, the amount of collagen in the regenerating liver of CCl4-treated rats whose liver regeneration was accelerated by TRQ was not different from that in the normal liver. These results suggest that TRQ has the effect of improving the various hepatic functions through the activation of the protein synthesis in hepatocytes.

Animals↗
PubMed2001

Androgen metabolism in regenerating liver of male rats: evidence for active uptake and utilization of testosterone.

The role of androgen in the regenerative process of the liver remains unclear. Male Sprague-Dawley rats were subjected to either 70% hepatectomy or sham operation. Immediately after surgical procedures, rats were injected with 0.3 µCi/g of body weight [3H]-testosterone from the inferior vena cava. The radioactivities of the remnant liver were counted for 0-24 h. For measurement of sex hormones and their metabolizing enzymes activities in the regenerating liver, the same experiments were also conducted, in which the rats were sacrificed up to 120 h. The plasma and hepatic testosterone, dihydrotestosterone(DHT) and estradiol were determined by radioimmunoassays. Uptake of [3H]-testosterone in the regenerating liver was significantly higher during the first 6 h. 5alpha-reductase I and DHT were increased in parallel to the hepatocyte proliferation which was assessed by proliferating cell nuclear antigen (PCNA) labeling index. On the other hand, hepatic 3alpha-hydroxysteroid dehydrogenase level did not alter but aromatase activity significantly decreased after 70% hepatectomy. These results suggest that during the early phase of liver regeneration, testosterone was actively uptaken from the plasma by the regenerating liver and was converted into DHT by elevated hepatic 5alpha-reductase enzyme. Thus androgens might play a crucial role in liver regeneration.

Journal Article↗
PubMed1985

[Liver regeneration at different stages of mononuclear infiltration induced by zymosan granules].

The relationship between regeneration of the liver of (CBA X C57BL)F1 mice and the degree of its mononuclear infiltration was studied. Resection of the 2/3 of the liver mass was performed 1 and 5 days and 2 months after zymosan-induced mononuclear infiltration. The synthesis of DNA and mitotic activity of hepatocytes in the liver with infiltrations was higher as compared with control. The rate of liver regeneration was dependent on the scope of the mononuclear infiltration, reaching a maximum provided liver resection was made 5 days after injection of zymosan granules.

Animals↗
PubMed1998

Plasma-kallikrein clearance during liver regeneration after partial hepatectomy in the rat.

AIMS/BACKGROUND: The liver clears circulating plasma-kallikrein through a receptor-mediated endocytosis process: an initial fast phase is followed by a slow exponential phase. METHODS: To determine whether the clearance rate of plasma-kallikrein is affected during liver regeneration, we perfused isolated rat livers with rat plasma-kallikrein (rPK) at 0, 1, 2, 3 and 7 days after partial hepatectomy or sham operation. RESULTS: Liver regeneration was followed by the expression of the proliferating-cell nuclear antigen (PCNA) labeling index. The serum concentration of alpha2-macroglobulin, an acute phase protein in rats, was measured. At day 1, the fast phase of rPK clearance rate increased in hepatectomized rats when compared with day 0 (4.9+/-0.4 and 3.7+/-0.4 mU/g liver min, p<0.05). However, at day 2, the rPK fast phase clearance rate dropped significantly (2.6+/-0.2, p<0.05), when compared with day 1. No difference was found among the sham groups at different days of hepatectomy. These changes seem to be independent of the acute phase reaction. The regenerative liver weight increased continuously during the observation period. PCNA expression increased significantly after hepatectomy, with maximal PCNA-labeling indices at days 1 and 2, declining thereafter. CONCLUSION: The rPK fast phase clearance rate changes during liver regeneration, with a zenith occurring when PCNA labeling index is maximal (day 1) and a nadir occurring at the mitotic phase (day 2).

Animals↗
PubMed1997

Changes of nuclear PI-PLC gamma1 during rat liver regeneration.

We have previously demonstrated that rat liver nuclei contain PI-PLC beta1 and gamma1 in the inner nuclear matrix and lamina associated with specific phosphodiesterase activity (Bertagnolo et al., 1995, Cell Signall. 7, 669-678). Since compensatory hepatic growth is an informative and well characterized model for natural cell proliferation, the presence of specific PI-PLC isoforms and their activity as well as PIP2 recovery were studied at various regenerating times, ranging from 3 to 22 h after partial hepatectomy. Three PI-PLC isoforms (beta1, gamma1, delta1) were examined in control and regenerating liver cells by using specific antibodies. By means of in situ immunocytochemistry and confocal microscopy, PI-PLC beta1 was found mainly in the nucleoplasm and this pattern was not modified after hepatectomy. On the contrary, the nuclear gamma1 isoform showed a marked decrease at 3 and 16 h after hepatectomy, but a clear increase at 22 h covering with bright intensity the whole nucleus. The PI-PLC delta1 isoform, which is exclusively cytoplasmic, was not altered during rat liver regeneration. By western blotting analysis on whole cell homogenates, none of the PI-PLC isozymes under study showed proliferation-linked modification. However, analyses of isolated nuclei identified changes in the nucleus associated PI-PLC gamma1 that paralleled the in situ observation whereas the beta1 isoform was unmodified at all the times examined. Nuclear phosphodiesterase activity on PIP2 was lower at 3 and 16 h, in comparison with sham operated rats, increased at 6 h and reached the highest value after 22 h. Consistently, the recovery of PIP2, obtained in conditions that optimise PIP-kinase activity, showed a marked decrease at 3 h and an increase up to 16 h of liver regeneration, followed by a further decrease at 22 h. These data are consistent with a close relationship between cell proliferation and the nuclear inositide cycle, depending, in rat liver, predominantly on the modulation of the gamma1 isoform of PI-PLC.

Animals↗
PubMed1981

Laminin and fibronectin in cell adhesion: enhanced adhesion of cells from regenerating liver to laminin.

Laminin, a basement membrane glycoprotein isolated from cultures of mouse endodermal cells and rat yolk sac carcinoma cells, promoted the attachment of liver cells obtained from regenerating mouse liver. Cells from normal mouse liver attached readily to dishes coated with fibronectin but attached poorly to surfaces coated with laminin. Both proteins efficiently promoted the attachment of cells from livers undergoing regeneration. After regeneration, the attachment to laminin returned to the low levels found in animals not subjected to partial hepatectomy but attachment to fibronectin remained high. Immunofluorescent staining of sections of normal liver with antilaminin revealed the presence of laminin in or adjacent to the walls of the bile ducts and blood vessels. After induction of regeneration by partial hepatectomy, increased amounts of laminin appeared in the sinusoidal areas. After carbon tetrachloride poisoning, staining for laminin was especially pronounced in the necrotic and postnecrotic areas around the central veins. This additional expression of laminin was transient. It reached a maximum around 5--6 days after the injury and then gradually disappeared. These findings show that laminin is an adhesive protein. The increase of laminin in regenerating liver and the adhesiveness of cells from such livers to laminin suggest a role for laminin in the maintenance of a proper tissue organization during liver regeneration.

Animals↗
PubMed1984

Modification of the intramolecular turnover of terminal carbohydrates of dipeptidylaminopeptidase IV isolated from rat-liver plasma membrane during liver regeneration.

An intramolecular turnover of the terminal carbohydrates L-fucose, N-acetylneuraminic acid and D-galactose is a characteristic property of several liver plasma membrane glycoproteins, first demonstrated for dipeptidylaminopeptidase IV (EC 3.4.14.5., DPP IV). The core carbohydrates D-mannose and N-acetyl-D-glucosamine turn over like the polypeptide chain. The ratio of apparent half-lives of L-fucose and L-methionine of DPP IV is shifted from 0.17 in normal liver to 0.60 in regenerating liver. The ratio of half-lives of N-acetylneuraminic acid and L-methionine is only slightly changed from 0.43 in normal liver to 0.61 in regenerating liver. The ratio of apparent half-lives of D-mannose and L-methionine amounts to 0.80 in normal liver and 0.71 after partial hepatectomy. From this a drastic reduction of the intramolecular turnover of L-fucose on plasma membrane DPP IV in regenerating liver can be derived. The intramolecular N-acetylneuraminic acid turnover is affected to only a minor extent. D-Mannose turns over like the polypeptide in both normal and regenerating liver. The intramolecular L-fucose turnover may be involved in membrane glycoprotein recycling, which presumably is altered in regenerating liver. Additionally, L-fucose could regulate the rate of degradation of DPP IV, since core-fucosylated glycoproteins appear to be resistant to mammalian endo-N-acetylglucosaminidase.

Animals↗
PubMed1985

Restriction of gut-derived endotoxin impairs DNA synthesis for liver regeneration.

The influence of restricting gut-derived endotoxin availability on liver regeneration after partial hepatectomy was evaluated. Partial hepatectomy was performed by 67% liver resection of ether-anesthetized rats. Liver regeneration was quantified after partial hepatectomy by [3H]thymidine incorporation into hepatic DNA; endotoxemia due to absorption of endogenous endotoxin from the gut into the portal circulation was determined by qualitative lysate assay of perchloric acid-extracted plasma samples, and plasma levels of the hepatotrophic factors insulin and glucagon were measured by radioimmunoassay. Treatments to restrict gut-derived endotoxin included chronic gavage with neomycin and cefazolin for gut sterilization, chronic gavage with cholestyramine to bind endotoxin within the gut, subcutaneous administration of polymyxin B to neutralize the lipid A portion of circulating endotoxin, intraperitoneal induction of endotoxin tolerance by progressively higher doses of endotoxin, and experimentation with isolator-reared defined flora Fisher rats that were Gram-negative bacteria deficient and therefore endotoxin deficient. All treatments to restrict endogenous endotoxin impaired DNA synthesis in regenerating livers particularly 21 h posthepatectomy when replication was increasing most rapidly in normal rats. We hypothesize that impairment of DNA synthesis after partial hepatectomy in endotoxin-restricted animals was due to the observed lack of normal systemic endotoxemic as well as hyperinsulinemic and hyperglucagonemic responses to 67% liver resection.

Animals↗
PubMed2004

Increased methylation of the cytosolic 20-kD protein is accompanied by liver regeneration in a hepatectomized rat.

Arginine methylation has been implicated in the signal transduction pathway leading to cell growth. Here we show that a regenerating rat liver following partial hepatectomy exhibited elevated methyltransferase activity as shown by increased methylation of a subset of endogenous proteins in vitro. The 20-kDa protein was shown to be a major cytosolic protein undergoing methylation in regenerating hepatocytes. Methylation of the 20-kDa protein peaked at 1 d following partial hepatectomy, which gradually declined to a basal level within the next 14 d. Likewise, methylation of exogenously added bulk histones followed the similar time kinetics as the 20-kDa protein, reflecting time-dependent changes in methyltransferase activity in regenerating hepatocytes. Presence of exogenously added bulk histone in the in vitro methylation assay resulted in dose-dependent inhibition of methylation of the 20-kDa protein. All the histone subtypes tested, histone 1, 2A, 2B, 3 or 4, were able to inhibit methylation of the 20-kDa protein while addition of cytochrome C, a-lactalbumin, carbonic anhydrase, bovine serum albumin, and g globulin minimally affected methylation of the 20-kDa protein. Since methylation of the 20-kDa protein preceded proliferation of hepatocytes upon partial hepatectomy, it is tempting to speculate that the methylated 20-kDa protein by activated histone-specific methyltransferase may be involved in an early signal critical for liver regeneration.

Animals↗
PubMed1998

A novel hepatic stellate (Ito) cell-derived protein, epimorphin, plays a key role in the late stages of liver regeneration.

Limited data exist regarding morphogenesis and differentiation during liver regeneration. We examined the role of epimorphin on liver regeneration. After 70% partial hepatectomy, mouse liver was collected on days 1, 3, 7, and 14 for immunohistochemistry and the detection of epimorphin mRNA and connexin 32. Using primary cultured rat hepatocytes, morphogenesis and differentiation of cells were tested with or without epimorphin. Seven days after cell inoculation, the expression of connexin 32 and the cell-cell communication was tested as a marker of differentiation. Epimorphin was detected exclusively in hepatic stellate cells. Connexin 32 was detected only in hepatocytes. After partial hepatectomy, epimorphin mRNA was detected on day 3 and peaked at day 7, followed by protein expression. Connexin 32 expression showed a similar time course. Cultured hepatocytes formed multicellular spheroids in an active epimorphin-coated culture dish and showed positive dye coupling, whereas the cell-cell communication was lost without active epimorphin. Because epimorphin was expressed late in liver regeneration, it might play a role in morphogenesis and differentiation.

Animals↗