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PubMed1984

Liver regeneration in oral contraceptive treated female rats--effects of moderate malnutrition.

Treatment of well-nourished female rats with a combination of 5 micrograms ethynyl estradiol and 100 micrograms ethynodiol diacetate, increased the DNA content, 3H thymidine incorporation into DNA and mitotic activity in the non-regenerating liver, but impaired liver regeneration after partial hepatectomy. In rats which were moderately malnourished by feeding 25 percent less calories and 50 percent of recommended allowance for vitamins A and B2, OC treatment had similar stimulatory effect on non-regenerating liver, but did not impair liver regeneration after partial hepatectomy. Analysis of nucleotide bases after hydrolysis of unpolymerized nucleotides and nucleosides revealed significant perturbations due to OC treatment. However, the impaired liver regeneration due to OC treatment of well-nourished rats could not be attributed to diminished availability of bases, particularly thymidine. Data on mitotic index and binucleate cell numbers suggest that besides inhibiting mitosis (DNA duplication), OC treatment of well-nourished rats may also impair partitioning of binucleate cells.

Animals↗
PubMed1998

Lack of coordinate control of ferritin and transferrin receptor expression during rat liver regeneration.

Transferrin receptor (TfR) and ferritin, key proteins of cellular iron metabolism, are coordinately and divergently controlled by cytoplasmic proteins (iron regulatory proteins, IRP-1 and IRP-2) that bind to conserved mRNA motifs called iron-responsive elements (IRE). IRP, in response to specific stimuli (low iron levels, growth and stress signals) are activated and prevent TfR mRNA degradation and ferritin mRNA translation by hindering ferritin mRNA binding to polysomes. We previously found that, in regenerating liver, IRP activation was accompanied by increased TfR mRNA levels, but not by reduced ferritin expression. The basis for this unexpected behavior was investigated in the present study. Liver regeneration triggered by carbon tetrachloride (CCl4) stimulated by four- to fivefold the synthesis of both L and H ferritin chains. This increase was accompanied with a transcriptionally regulated twofold rise in the amount of ferritin mRNAs. Moreover, polysome-associated ferritin transcripts were fourfold higher in CCl4-treated animals than in control animals. Because RNA bandshift assays showed a fourfold increase in IRP-2 binding activity after CCl4 administration, activated IRP in regenerating liver seemed unable to prevent ferritin mRNAs binding to polysomes. This was confirmed by direct demonstration in the wheat germ translation system that the efficiency of IRP as a translational repressor of a mRNA bearing an IRE motif in front of a reporter transcript is impaired in CCl4-treated rats in spite of an enhanced IRE-binding capacity. In conclusion, we show for the first time that the paradigm of coordinate and opposite control of ferritin and TfR by IRP is contradicted in liver regeneration. Under these circumstances, growth-dependent signals may activate ferritin gene transcription and at the same time hamper the ability of activated IRP-2 to repress translation of ferritin mRNAs, thus preserving for growing liver cells an essential iron-storage compartment.

Animals↗
PubMed1984

Retinyl palmitate, retinyl phosphate, and dolichyl phosphate of postnuclear membrane fraction from hepatoma, host liver, and regenerating liver: marginal vitamin A status of hepatoma tissue.

The retinyl palmitate content of the postnuclear membrane fraction from 10 Morris hepatomas, their host rat livers, one acetylaminofluorene-induced rat liver hepatoma, and the host liver and of regenerating rat liver was measured by reverse-phase high-pressure liquid chromatography of the chloroform:methanol extracts. Membranes from the hepatoma tissue contained less than detectable levels of retinyl acyl esters, whereas membranes from host liver tissue and regenerating liver contained levels of retinyl palmitate within normal ranges. The amount of cellular retinol-binding protein was also decreased considerably in cytosols from 9618 and 7777 hepatomas. The ratio of endogenous retinyl phosphate to the polyisoprenoid dolichyl phosphate available for mannosylation in an assay containing postnuclear membranes and guanosine dephospho[14C] mannose was decreased by a factor of 3 to 10 in hepatoma tissue. Such change in ratio was not attributable to specific changes in retinyl phosphate mannose-synthesizing activity, but it appeared to be related to the vitamin A deficiency condition of the membrane from tumors. As for membranes from vitamin A-deficient liver tissue, postnuclear membranes from rat cystic hepatocarcinoma, Morris 7777, 3924A1-1, and 5123D-1-2 transplantable rat hepatomas and guinea pig line 10 hepatoma all synthesized a mannolipid with intermediate hydrophobic properties between retinyl phosphate mannose and dolichyl phosphate mannose and not normally found in liver tissue. These alterations in patterns of lipid intermediates may be responsible for altered glycosylation of glycoproteins in neoplastic cells. In conclusion, the present investigation establishes that hepatoma cell membrane is in a status of vitamin A and of retinyl phosphate depletion, while dolichyl phosphate contents appear similar to host liver membrane.

Animals↗
PubMed1991

Identification of LRF-1, a leucine-zipper protein that is rapidly and highly induced in regenerating liver.

Liver regeneration provides one of the few systems for analysis of mitogenesis in the fully developed, intact animal. Several proteins have been identified as part of the primary growth response in regenerating liver and in mitogen-stimulated cells. Some of these proteins, such as the Jun and Fos families of transcription factors, are thought to have a role in activating transcription of genes expressed subsequently in the growth response. Through differential screening of a regenerating-liver cDNA library, we have identified a rapidly and highly induced gene encoding a 21-kDa leucine-zipper-containing protein that we have designated liver regeneration factor 1 (LRF-1). LRF-1 has no homology with other leucine-zipper proteins outside the basic and leucine-zipper domains. LRF-1 alone can bind DNA, but it preferentially forms heteromeric complexes with c-Jun and Jun-B and does not interact with c-Fos. In solution, it binds with highest affinity to cAMP response elements but also has affinity for related sites. In cotransfection studies, LRF-1 in combination with c-Jun strongly activates a c-Jun-responsive promoter. The induction of the LRF-1 gene in regenerating liver greatly increases the potential variety of heterodimeric combinations of leucine-zipper transcription factors. While LRF-1 mRNA is rapidly induced in the absence of protein synthesis, its peak induction is later than c-fos mRNA, suggesting that LRF-1 may regulate responsive genes at a later point in the cell cycle. As such, LRF-1 may have a unique and critical role in growth regulation of regenerating liver and mitogen-stimulated cells.

Activating Transcription Factor 3↗
PubMed2006

Expression patterns and action analysis of genes associated with blood coagulation responses during rat liver regeneration.

AIM: To study the blood coagulation response after partial hepatectomy (PH) at transcriptional level. METHODS: After PH of rats, the associated genes with blood coagulation were obtained through reference to the databases, and the gene expression changes in rat regenerating liver were analyzed by the Rat Genome 230 2.0 array. RESULTS: It was found that 107 genes were associated with liver regeneration. The initially and totally expressing gene numbers occurring in initiation phase of liver regeneration (0.5-4 h after PH), G0/G1 transition (4-6 h after PH), cell proliferation (6-66 h after PH), cell differentiation and structure-function reconstruction (66-168 h after PH) were 44, 11, 58, 7 and 44, 33, 100, 71 respectively, showing that the associated genes were mainly triggered in the forepart and prophase, and worked at different phases. According to their expression similarity, these genes were classified into 5 groups: only up-, predominantly up-, only down-, predominantly down-, up- and down-regulation, involving 44, 8, 36, 13 and 6 genes, respectively, and the total times of their up- and down-regulation expression were 342 and 253, respectively, demonstrating that the number of the up-regulated genes was more than that of the down-regulated genes. Their time relevance was classified into 15 groups, showing that the cellular physiological and biochemical activities were staggered during liver regeneration. According to gene expression patterns, they were classified into 29 types, suggesting that their protein activities were diverse and complex during liver regeneration. CONCLUSION: The blood coagulation response is enhanced mainly in the forepart, prophase and anaphase of liver regeneration, in which the response in the forepart, prophase of liver regeneration can prevent the bleeding caused by partial hepatectomy, whereas that in the anaphase contributes to the structure-function reorganization of regenerating liver. In the process, 107 genes associated with liver regeneration play an important role.

Animals↗
PubMed1996

Liver regeneration 4: transcriptional control of liver regeneration.

Determining what factors are responsible for initiating regeneration following partial hepatectomy or toxic damage, and how the liver maintains differentiated functions while the hepatocytes are undergoing cellular proliferation are central issues in understanding the molecular bases of liver regeneration. Examination of the transcriptional milieu in the regenerating liver provides clues to the answers to these questions. Growth factor-generated intracellular signals that trigger liver regeneration result in activation via posttranslational modifications of latent, normally inactive transcription factors that preexist in the liver. Two transcription factors that are activated by this mechanism include posthepatectomy factor/nuclear factor-kappa B) and Stat3. Because cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-l (IL-1), and IL-6 can induce these factors in the liver, the finding of activated Stat3 and PHF/NF-kappa B suggests that these cytokines may play a role in some aspects of growth regulation during liver regeneration. Rapidly induced transcription factors, Stat3, PHF/NF-kappa B, and others are responsible for activation of the primary growth response or immediate-early genes, which play a role in regulating later phases of cell growth in regenerating liver and other mitogen-activated cells. Immediate-early genes encode many members of diverse transcription factor families including the Jun-Fos-LRF-1, nuclear receptor, and myc families to name a few. In this way a transcriptional cascade is established during the G1 phase of liver regeneration. Coexisting with these induced factors are liver-specific transcription factors such as the CAAT enhancer binding proteins and hepatocyte nuclear factors, which may interact with growth-induced factors to help the liver maintain metabolic homeostasis during regeneration. As a result the liver is able to accomplish the goals of reestablishing its mass while it maintains its functional capacity during regeneration.

Animals↗
PubMed1993

RNR-1, a nuclear receptor in the NGFI-B/Nur77 family that is rapidly induced in regenerating liver.

Liver regeneration following partial hepatectomy provides one of the few systems for analysis of mitogenesis in the fully developed, intact animal. Immediate-early growth response genes, induced in the absence of prior protein synthesis, play an important regulatory role in the regenerative process. During screening of a subtracted cDNA library of immediate-early genes induced during liver regeneration, a novel member of the thyroid/steroid receptor superfamily, RNR-1 (regenerating liver nuclear receptor), was identified. This gene is not expressed in quiescent liver but is rapidly induced following partial hepatectomy and is specific to hepatic growth as it is not induced in other mitogen-treated cells. RNR-1 is also expressed in brain. A full-length cDNA clone of RNR-1 encodes a 66-kDa, 597-amino acid protein as verified by in vitro translation in reticulocyte lysate. RNR-1 is highly homologous to r-NGFI-B/m-Nur77 particularly in the DNA binding (94%) and putative ligand binding (59%) domains. Using a mobility shift assay, we have shown that RNR-1 specifically binds to the NGFI-B DNA half-site and forms a complex very similar in size to the Nur77 complex, suggesting that RNR-1 also may bind as a monomer. Consistent with this finding, the A box region important in mediating half-site binding is 100% conserved between r-NGFI-B/m-Nur77. Both RNR-1 and Nur77 strongly transactivate a reporter driven by a consensus r-NGFI-B/Nur77 binding site, and their effect together is additive. As both the RNR-1 and r-NGFI/m-nur77 genes are induced during liver regeneration, it is very possible that RNR-1 acts concomitantly with r-NGFI/m-Nur77 in regulating the expression of delayed-early genes during liver regeneration.

3T3 Cells↗
PubMed1995

Both coding exons of the c-myc gene contribute to its posttranscriptional regulation in the quiescent liver and regenerating liver and after protein synthesis inhibition.

In vivo, the steady-state level of c-myc mRNA is mainly controlled by posttranscriptional mechanisms. Using a panel of transgenic mice in which various versions of the human c-myc proto-oncogene were under the control of major histocompatibility complex H-2Kb class I regulatory sequences, we have shown that the 5' and the 3' noncoding sequences are dispensable for obtaining a regulated expression of the transgene in adult quiescent tissues, at the start of liver regeneration, and after inhibition of protein synthesis. These results indicated that the coding sequences were sufficient to ensure a regulated c-myc expression. In the present study, we have pursued this analysis with transgenes containing one or the other of the two c-myc coding exons either alone or in association with the c-myc 3' untranslated region. We demonstrate that each of the exons contains determinants which control c-myc mRNA expression. Moreover, we show that in the liver, c-myc exon 2 sequences are able to down-regulate an otherwise stable H-2K mRNA when embedded within it and to induce its transient accumulation after cycloheximide treatment and soon after liver ablation. Finally, the use of transgenes with different coding capacities has allowed us to postulate that the primary mRNA sequence itself and not c-Myc peptides is an important component of c-myc posttranscriptional regulation.

Animals↗
PubMed2004

Apoptosis induced by 5-(N,N-hexamethylene)-amiloride in regenerating liver after partial hepatectomy.

The effects of a specific inhibitor of the Na+/H+ exchanger, 5-(N,N-hexamethylene)-amiloride (HMA), on liver regeneration after partial hepatectomy were investigated. A single injection of HMA inhibited DNA synthesis and caused apoptosis in regenerating liver. Characteristic DNA fragmentation was observed at 4 h after partial hepatectomy with HMA-injection. The activity of Jun N-terminal kinase (JNK) increased to a maximal level at 15 min after partial hepatectomy in HMA-injected rats, while it was not detected until 30 min in the control. Western blot analysis revealed that the injection of HMA markedly increased c-Jun and phosphorylated c-Jun protein levels at 30 min after partial hepatectomy. An increase in p53 was also observed at 30 min after the HMA-injection and was followed by the upregulation of p21WAF1/CIP1 protein expression at 1 h after partial hepatectomy. These results suggested that HMA induced apoptosis accompanied by the activation of JNK and the upregulation of c-Jun, p53 and p21WAF1/CIP1 expression at an early stage of liver regeneration.

Amiloride↗
PubMed1990

c-myc, c-fos, and c-jun regulation in the regenerating livers of normal and H-2K/c-myc transgenic mice.

We investigated the mechanisms of regulation of c-myc, c-fos, and c-jun at the early stages of liver regeneration in mice. We show that the transient increase in steady-state levels of c-myc mRNA at the start of liver regeneration is most probably regulated by posttranscriptional mechanisms. Although there was a marked increase in c-myc transcriptional initiation shortly after partial hepatectomy, a block in elongation prevented the completion of most transcripts. To gain further information on the mechanism of regulation of c-myc expression during liver regeneration, we used transgenic mice harboring the human c-myc gene driven by the H-2K promoter. In these animals, the murine c-myc responded to the growth stimulus generated by partial hepatectomy, whereas the expression of the transgene was constitutive and did not change in the regenerating liver. However, the mRNA from both genes increased markedly after cycloheximide injection, suggesting that the regulation of c-myc mRNA abundance in the regenerating liver differs from that occurring after protein synthesis inhibition. Furthermore, we show that in normal mice c-fos and c-jun mRNA levels and transcriptional rates increase within 30 min after partial hepatectomy. c-fos transcriptional elongation was restricted in nongrowing liver, but the block was partially relieved in the regenerating liver. Nevertheless, for both c-fos and c-jun, changes in steady-state mRNA detected after partial hepatectomy were much greater than the transcriptional increase. In the regenerating liver of H-2K/c-myc mice, c-fos and c-jun expression was diminished, whereas mouse c-myc expression was enhanced in comparison with that in nontransgenic animals.

Animals↗
PubMed1991

[Effect of LAK cells on liver regeneration after partial hepatectomy].

Lymphokine activated killer (LAK) cells can destroy not only tumor cells but also syngeneic regenerating liver cells. This study was started to determine the effect of passive transfer of LAK cells on liver regeneration after partial hepatectomy. C3H mice were received 70% hepatectomy and LAK cells were injected intravenously at a dose of 5 X 10(7) cells/body. After 36 hours, 3H-thymidine uptake into the residual liver was measured. LAK cells transferred group showed 31% suppression compared with control group. In vitro, 24 hours addition of LAK cells to the primary culture of regenerating liver cells caused 97% suppression of 3H-thymidine uptake at effector to target ratio, 50/1. Then we examined the effects of IL-2 administration on liver regeneration. Though IL-2 showed no effect on cultured liver cells, intraperitoneal administration of IL-2 after hepatectomy at a dose of 1 X 10(4)u/body 5 times every 8 hours brought 38% suppression of 3H-thymidine uptake of the residual liver. Cyclosporine A, which can suppress the IL-2 production of lymphocytes, promoted liver regeneration 45% over the control at a dose of 10 mg/kg. These results suggest that LAK cells could regulate liver regeneration.

Animals↗
PubMed1984

An induction of heme oxygenase and its possible relation to the decrease of cytochrome P-450 content during liver regeneration.

The alterations of various enzymes responsible for drug metabolism and heme metabolism were examined in regenerating livers of male rats. Microsomal cytochrome P-450 content and aminopyrine demethylase activity were significantly decreased during liver regeneration. In contrast, microsomal heme oxygenase activity was markedly increased under the identical conditions. The increased heme oxygenase activity which appeared within 4 h and reached maximum at 1 d after partial hepatectomy was sustained for 5 d. In sham-operated rats, the changed patterns of these parameters were similar, but to a lesser extent as compared to partially hepatectomized rats. The increase of heme oxygenase activity following partial hepatectomy was blocked by the administration of cycloheximide or actinomycin D. Other enzymes involved in heme synthesis did not change appreciably during liver regeneration. The inverse relationship between the decrease of cytochrome P-450 content and the increase of heme oxygenase activity was also observed in female rats and male mice. These findings suggest that the increase of heme oxygenase activity in regenerating rodent liver would be correlated to the decrease of cytochrome P-450 content. Adrenalectomy enhanced the increase of heme oxygenase activity following partial hepatectomy, though the decrease of cytochrome P-450 content was less extensive under the experimental conditions. The results also suggest that the inverse relationship between the increase of heme oxygenase activity and the decrease of cytochrome P-450 content would be a biochemical phenomenon seen in regenerating liver and that the phenomenon would not be simply due to the surgical stress to the animals.

Adrenalectomy↗
PubMed2000

Augmenter of liver regeneration (ALR) may promote liver regeneration by reducing natural killer (NK) cell activity in human liver diseases.

Cytotoxicity of liver natural killer cells against regenerating hepatocytes has been reported as a possible mechanism of regeneration failure in fulminant hepatitis. An augmenter of liver regeneration (ALR) inhibits liver natural killer cell activity in rats. In this study, we measured hepatic expression of ALR mRNA, blood levels of ALR, and peripheral blood natural killer cell activity in patients with various types of acute liver disease to investigate the relationship between failure of liver regeneration and hepatic natural killer cells. Hepatic ALR mRNA expression was higher in liver disease patients than in non-liver disease controls, and a correlation was found between serum ALR values and hepatic levels of ALR mRNA. In acute liver injury, the serum ALR level also showed a negative correlation with NK activity. ALR was produced by and released from the liver at the time of hepatic injury. Our findings suggest that ALR may protect against failure of regeneration by inhibition of hepatic natural killer cell activity in acute liver injury.

Antibodies↗
PubMed2003

Gene and protein expressions of p28GANK in rat with liver regeneration.

AIM: To observe the gene and protein expression changes of p28GANK in regenerating liver tissues, and to reveal the biological function of p28GANK on the regulation of liver regeneration. METHODS: One hundred and thirty two adult male Sprague-Dawley rats were selected, weighing 200-250 g, and divided randomly into sham operation (SO) group and partial hepatectomy (PH) group. Each group had eleven time points: 0, 2, 6, 12, 24, 30, 48, 72, 120, 168 and 240 h, six rats were in each time point. The rats were undergone 70% PH under methoxyflurane anesthesia by resection of the anterior and left lateral lobes of the liver. SO was conducted by laparotomy plus slight mobilization of the liver without resection. Liver specimens were collected at the indicated time points after PH or SO. The expression level of p28GANK mRNA was determined by Northern blot as well as at protein level via immunohistochemical staining. The expressions of p28GANK mRNA in these tissues were analyzed by imaging analysis system of FLA-2000 FUJIFILM and one way analysis of variance. The protein expressions of p28GANK in these tissues were analyzed with Fromowitz' method and Rank sum test. RESULTS: The expression of p28GANK mRNA in the regenerating liver tissues possessed two transcripts, which were 1.5 kb and 1.0 kb. There was a significantly different expression patterns of p28GANK mRNA between SO and PH groups (P<0.01). The expression of p28GANK mRNA increased 2 h after PH, the peak time was 72 h (SO group: 163.83+/-1.4720; PH group: 510.5+/-17.0499, P<0.01). There was a significant difference in the 1.5 kb transcript, which decreased gradually after 72 hours. The protein expression of p28GANK was mainly in the cytoplasm of regenerating hepatocytes, and increased near the central region 24 h after PH, and became strongly positive at 48 h (+++, vs the other time points P<0.05), but decreased 72 h after PH. CONCLUSION: The expression of p28GANK mRNA increases in the early stage of rat liver regeneration, the protein expression of p28GANK is mainly in the cytoplasm of regenerating liver cells. It suggests that the gene of p28GANK may be an important regulatory and controlled factor involved in hepatocyte proliferation during liver regeneration.

Animals↗
PubMed2006

Hepatocytes with extensive telomere deprotection and fusion remain viable and regenerate liver mass through endoreduplication.

We report that mouse liver cells are highly resistant to extensive telomere dysfunction. In proliferating cells, telomere dysfunction results in chromosome end fusions, a DNA damage signal, and apoptosis or senescence. To determine the consequences of telomere dysfunction in noncycling cells, we used conditional deletion of the telomeric protein TRF2 in hepatocytes. TRF2 loss resulted in telomeric accumulation of gamma-H2AX and frequent telomere fusions, indicating telomere deprotection. However, there was no induction of p53 or apoptosis, and liver function appeared unaffected. Furthermore, the loss of TRF2 did not compromise liver regeneration after partial hepatectomy. Remarkably, liver regeneration occurred without cell division involving endoreduplication and cell growth, thereby circumventing the chromosome segregation problems associated with telomere fusions. We conclude that nondividing hepatocytes can maintain and regenerate liver function despite substantial loss of telomere integrity.

Animals↗