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PubMed2005

Quantitative gene expression analysis by cDNA microarray during liver regeneration after partial hepatectomy in rats.

PURPOSE: It is speculated that genetic regulation plays an important role during liver regeneration. We conducted this study to analyze quantitative gene expression during liver regeneration after partial hepatectomy. METHODS: Sixty male Wistar rats were randomly assigned into ten groups of six. One group of rats was killed preoperatively and the other nine groups were killed 2, 4, 6, 12, 24, 48, and 72 h, and 5 and 7 days after 70% partial hepatectomy, respectively. The remnant livers were isolated for mRNA extraction. A mass survey of gene expression by cDNA microarray carrying 6144 polymerase chain reaction-amplified cDNA fragments was prepared by an arraying machine. The microarray images were scanned, digitized, and analyzed using a flatbed scanner. RESULTS: The variations in gene expression were classified into 72 different patterns including a pattern with a single peak, 2, 4, 6, 12, and 72 h, and 5 and 7 days after partial hepatectomy. The other patterns included double peaks, enhancing trend, diminished trend, protruding curve, excavated curve, and various mixed types. Each category of gene expression pattern contained 40-218 different proto-oncogenes. CONCLUSION: The quantitative gene expression profiles have important implications, warranting further investigation of the genetic mechanisms involved in the process of liver regeneration.

Animals↗
PubMed2006

Proliferative effect of the aqueous extract of Hyptis pectinata on liver regeneration after partial hepatectomy in rats.

PURPOSE: This study was carried out to assess the effects of the aqueous extract of Hyptis pectinata leaves on liver regeneration and on serum enzymes (AST, ALT and gamma-GT) after 67% partial hepatectomy in rats. METHODS: AST, ALT and gamma-GT, were determined by conventional procedures using a spectrophotometer (Model E2250-CELM). Liver regeneration was evaluated by immunohistochemical staining for proliferating cell nuclear antigen (PCNA). RESULTS: Oral pretreatment during 4 days at 100 mg/kg increased liver regeneration index. At 200 mg/kg, AST level was statistically decreased in comparison to the group submitted to distilled water administration. The other enzymes assessed disclosed no difference when all groups were compared. CONCLUSION: The present study shows that the aqueous extract of Hyptis pectinata leaves contains some biological active principles that stimulate liver regeneration at 100 mg/kg and cause slight hepatic protection at 200 mg/kg.

Animals↗
PubMed2006

Increased expression of hepatocyte nuclear factor 6 stimulates hepatocyte proliferation during mouse liver regeneration.

BACKGROUND & AIMS: The hepatocyte nuclear factor 6 (HNF6 or ONECUT-1) protein is a cell-type specific transcription factor that regulates expression of hepatocyte-specific genes. Using hepatocytes for chromatin immunoprecipitation (ChIP) assays, the HNF6 protein was shown to associate with cell cycle regulatory promoters. Here, we examined whether increased levels of HNF6 stimulate hepatocyte proliferation during mouse liver regeneration. METHODS: Tail vein injection of adenovirus expressing the HNF6 complementary DNA was used to increase hepatic HNF6 levels during mouse liver regeneration induced by partial hepatectomy, and DNA replication was determined by bromodeoxyuridine incorporation. Cotransfection and ChIP assays were used to determine transcriptional target promoters. RESULTS: Elevated expression of HNF6 during mouse liver regeneration causes a significant increase in the number of hepatocytes entering DNA replication (S phase), and mouse hepatoma Hepa1-6 cells diminished for HNF6 levels by small interfering RNA transfection exhibit a 50% reduction in S phase following serum stimulation. This stimulation in hepatocyte S-phase progression was associated with increased expression of the hepatocyte mitogen tumor growth factor alpha and the cell cycle regulators cyclin D1 and Forkhead box m1 (Foxm1) transcription factor. Cotransfection and ChIP assays show that tumor growth factor alpha, cyclin D1, and HNF6 promoter regions are direct transcriptional targets of the HNF6 protein. Coimmunoprecipitation assays with regenerating mouse liver extracts reveal an association between HNF6 and FoxM1 proteins, and cotransfection assays show that HNF6 stimulates Foxm1 transcriptional activity. CONCLUSIONS: These mouse liver regeneration studies show that increased HNF6 levels stimulate hepatocyte proliferation through transcriptional induction of cell cycle regulatory genes.

Adenoviridae↗
PubMed1986

Acceleration of liver regeneration by malotilate in partially hepatectomized rats.

The effect of malotilate (diisopropyl 1,3-dithiol-2-ylidenemalonate) on liver regeneration was studied by using partially hepatectomized rats. Malotilate administration (100 mg/kg/day, p.o.) facilitated the weight gain of the liver after partial hepatectomy. Protein, RNA and DNA contents of the regenerating liver correlated well with the weight gain. The weight gain, RNA and DNA contents, and mitotic index were significantly suppressed in the alloxan-diabetic rats 24 hr after partial hepatectomy. However, malotilate administration significantly improved the delayed recovery of RNA content. Other parameters were not significantly improved by malotilate, but tended to increase to a level comparable to those of partially hepatectomized control rats. These results show that malotilate accelerates cell proliferation, resulting in facilitated liver regeneration in rats (as well as in alloxan-diabetic rats).

Alloxan↗
PubMed1975

Liver regeneration after portacaval transportation in rats.

General recognition of the presence of a specific hepatotrophic factor in portal blood that is necessary for liver regeneration was delayed by two major problems. First, there was a long period of confusion regarding liver atrophy, liver hypertrophy, and cellular hyperplasia. Second, because only exposure to other liver tissue destroys the hepatotrophic activity, all of the studies that were based on bypassing the portal blood into the systemic circulation merely diluted the active substance, which still was available to the hepatocytes by recirculation through the hepatic artery. These problems have been resolved by the development of more sophisticated methods by which to assay liver regeneration and by the introduction of the double liver model to study regeneration. During the time when liver weight alone was used to assess regeneration, the regenerative capacity of the liver was reported to be much greater after portacaval transposition than after end-to-side portacaval shunt, a finding that is inconsistent with current knowledge of the hepatotrophic portal blood factor. To re-evaluate the effect on liver regeneration of providing a compensatory systemic venous inflow after complete portal diversion, 40 partially hepatectomized inbred rats which had previously undergone either a sham operation and end-to-side portacaval shunt or a portacaval transposition were compared on the basis of six separate criteria of regeneration. All of the livers actively regenerated and no significant advantage of providing a substitute systemic venous inflow to the liver could be detected by any of the criteria.

Animals↗
PubMed2002

Cloning and characterization of a mouse liver-specific gene mfrep-1, up-regulated in liver regeneration.

Human fibrinogen-related protein-1/liver fibrinogen-related protein-1 (HFREP-1/LFIRE-1), a liver-specific protein, is a member of fibrinogen superfamily that exerts various biological activities. However, the function of HFREP-1/LFIRE-1 in liver remains unknown. Here we isolated its mouse ortholog gene-mouse fibrinogen-related protein-1 (mfrep-1), which encoded 314 amino acids, exhibiting 80.4% similarity to HFREP-1/LFIRE-1. Northern blot analysis revealed that 1.2-kb mfrep-1 mRNA was detected selectively in mouse liver. To explore the function of MFREP-1, we examined the levels of mfrep-1 mRNA during regeneration after 70% partial hepatectomy (PHx) in mice. mfrep-1 mRNA increased in the regenerating liver and reached the first shoulder peak at 2-4 h after PHx. Cycloheximide pretreatment could suppress the induction of mfrep-1, indicating the up-regulation of this gene need de novo protein synthesis. Its mRNA continued to elevate at 6 h thereafter and reached the second peak at 24 h. The enhanced expression of mfrep-1 maintained high until 72 h and then declined slowly to the basal level. Immunohistochemistry assessment confirmed the up-regulated expression of MFREP-1 protein in parenchymal cells during liver regeneration. These data suggested that MFREP-1 might play an important role in liver regeneration and be involved in the regulation of cell growth.

Animals↗
PubMed1979

Effect of a single treatment with the alkylating carcinogens dimethylnitrosamine and methyl methanesulphonate on liver regenerating after partial hepatectomy. IV. Effect on methylase-mediated methylation of DNA.

The possibility that carcinogens may affect methylase-mediated methylation of replicating DNA was investigated. A system eminently suitable for this purpose is liver regenerating after partial hepatectomy, as one injection of dimethylnitrosamine (DMN) given during the ensuing period of increased DNA synthesis induces hepatocellular carcinoma. Methylation of DNA by DNA methylase normally occurs only in proportion to DNA synthesis. Therefore simultaneous measurements were made of synthesis (incorporation of [14C]adenine into DNA adenine, or of d[5-3H]cytidine into DNA cytosine), and of methylation (incorporation of [methyl-3H]methionine into 5-methylcytosine of DNA) in liver regenerating after partial hepatectomy. After treatment with DMN, the ratio of methylation: synthesis remained within the normal range. Methyl methanesulphonate (MMS), a compound which damages DNA in regenerating liver in a similar but not identical way to DMN and which does not induce tumors in liver even when given after partial hepatectomy, caused an increase in methylation in relation to synthesis. These experiments therefore do not support the view that altered DNA methylase activity is involved in carcinogenesis.

Animals↗
PubMed1993

Bile secretion and liver regeneration in partially hepatectomized rats.

OBJECTIVE: The purpose of this research was to study the correlation between bile secretion and the liver regeneration in the partially hepatectomized rat. SUMMARY BACKGROUND DATA: Significant alteration in bile formation and secretion is expected in the liver after hepatectomy. There is scant literature, however, about the effects of liver regeneration in bile secretion. METHODS: The work was done in rats with 50% hepatectomy, 75% hepatectomy, and sham operation as the control. A chronic common bile duct fistula and a duodenal cannula were established for bile collection and the sample analysis on days 1, 3, 5, 7, and 9. RESULTS: With size reduced in the liver after 50% and 75% hepatectomy, the total bile volume decreased 45.9% and 51.5%, bile salt independent flow decreased 59.3% and 64.9%, bile salt secretion rate decreased 36.1% and 43.4%, bile salt basal synthesis rate decreased 52.3% and 56.4%, phospholipid secretion rate decreased 52.6% and 68.0%, and cholesterol secretion rate decreased 54.3% and 72.4% from control on day 1, respectively. All changes returned to the control level in 3 to 9 days with accompanying increasing liver size during regeneration. CONCLUSION: Alterations of total bile flow, bile salt independent flow, bile salt secretion rate, bile salt basal synthesis rate, and biliary lipid secretion after partial hepatectomy correlate with the liver regeneration rate in rats. Partial hepatectomy reduces the bile salt independent fraction calculated as per 100 g body weight rather than the dependent fraction. The study of bile salt and biliary lipid secretion is a useful method for monitoring synthetic function in liver regeneration in vivo.

Animals↗
PubMed1979

Sequential analysis of hepatic carcinogenesis: a comparative study of the ultrastructure of preneoplastic, malignant, prenatal, postnatal, and regenerating liver.

The objective of this study was to compare the fine structure of presumptive preneoplastic hepatocytes at various times during liver carcinogenesis with that of normal, developing, and regenerating liver and of hepatocellular carcinomas, using transmission and scanning electron microscopy. A new model of liver carcinogenesis was used in which several of the early steps are quite well synchronized. A single initiating dose of diethylnitrosamine induced isolated islands of altered hepatocytes. The cells were characterized by persistence of glycogen despite starvation, increase in smooth endoplasmic reticulum, and hypertrophic nucleoli. Following intense selection of the altered hepatocytes by dietary 2-acetylaminofluorene plus partial hepatectomy, the affected hepatocytes proliferated rapidly to produce basophilic foci. These early hyperplastic lesions revealed stellate-shaped dilated bile canaliculi lined by blebs and abnormally thick elongated microvilli, a decreased number of microvilli on the sinusoidal surface, a marked increase in smooth endoplasmic reticulum, large nucleoli, and bundles of pericanalicular microfilaments. A majority of the proliferating lesions reacquired a normal organizational pattern within several weeks after partial hepatectomy and could not be distinguished from normal liver. A small number continued to grow and become typical persistent hyperplastic nodules. These showed significant widening of intercellular spaces between hepatocytes, elongated microvilli over large regions of the cell surface, many invaginations of the cell membrane, and irregularly shaped bile canaliculi. Sequential changes in focal hyperplastic hepatocytes during carcinogenesis could be distinguished from normal, developing, and regenerating liver. The major differences involved the cell surfaces and cytoplasmic organelles. The findings are compatible with the hypothesis that a carcinogen may act by inducing alterations in a small number of hepatocytes and that hepatocellular carcinomas arise through stepwise evolutional changes in these cells.

Animals↗
PubMed1989

Human growth hormone stimulates liver regeneration in rats.

To study the effect of human growth hormone (hGH) on liver regeneration in rats, 200 micrograms hGH was administered to partial hepatectomized rats twice a day for three days. The bw of hGH-treated rats was higher than that in untreated rats. After three day administration, the liver weight was 3.18 +/- 0.13 g, significant higher than that of untreated rats (2.68 +/- 0.17 g). Human GH also stimulated the mitosis in the liver. Serum insulin-like growth factor I (IGF-I) and albumin levels were significantly increased and urea nitrogen levels were significantly decreased in hGH-treated rats compared with those in untreated rats. When 120 micrograms/day IGF-I was continuously administered to partial hepatectomized rats for three days, the bw and the liver weight were not higher than those of controls. These data indicate that hGH directly stimulates liver regeneration and recover liver dysfunction in rats.

Animals↗
PubMed1990

Liver regeneration after partial hepatectomy: effects of glucose and branched-chain amino acid.

The phenomenon of liver regeneration has been observed within several days after partial hepatectomy, though there is still much controversy as to its initiation, regulation, and the control factors behind it. Male Wistar rats weighing around 200 g were used as subjects in this study. Partial hepatectomy with resection of the median and left lateral lobes (67.31%) was performed. High glucose, low glucose, or high or low branched-chain amino acid (BCAA) solutions were given intravenously 2 days prior to the partial hepatectomy. The rats were sacrificed at 6, 24, 48, and 72 hours after the operation. Remnant liver weight, Deoxyribonucleic acid (DNA) content, DNA synthesis rate, and mitotic index were chosen as markers for comparing the effects of the glucose and branched-chain amino acid solutions on liver regeneration. The results were as follows: (1) following removal of two-thirds of a rat's liver, DNA synthesis increased abruptly, peaking at 24 hours, the mitotic index reached a maximum at 48 hours, and the remaining lobes had doubled in size by 48 hours and had attained around 90% of the normal liver weight at 72 hours; (2) judging by the results of the remnant liver weight, DNA content, and DNA synthesis rate, the low glucose infusion rates showed the worst regenerative condition; and (3) the only effect of BCAA on liver regeneration observed was that low BCAA infusion rates resulted in a lower DNA content in the remnant liver.

Amino Acids, Branched-Chain↗
PubMedDate not supplied

Alpha 1-adrenergic effects and liver regeneration.

The effects of several treatments involving alpha-adrenergic mechanisms upon the early stages of rat liver regeneration were examined. Catecholamine concentrations in rat plasma were measured at various times after hepatectomy and were found to be elevated relative to those in plasma from sham-operated rats. Surgical hepatic denervation or injection of an alpha 1-adrenergic receptor antagonist (prazosin) reduced incorporation of [3H]thymidine into liver DNA during the first 24 hr after partial hepatectomy. Chronic guanethidine injections (3 to 6 weeks) reduced liver catecholamine levels, but did not affect its ability to regenerate. The inhibition of regenerative DNA synthesis by prazosin was preceded by an alteration in the binding of epidermal growth factor to regenerating liver, which was apparently the result of an increased number of epidermal growth factor receptors. Thus, alpha 1-adrenergic blockade, which affects both epidermal growth factor receptor binding and subsequent DNA synthesis in hepatocyte primary cultures, can also modulate these processes during liver regeneration in vivo.

Animals↗
PubMed2002

Hepatic branch vagotomy can block liver regeneration enhanced by ursodesoxycholic acid in 66% hepatectomized rats.

The effect of hepatic branch vagotomy on liver regeneration induced by ursodesoxycholic acid was examined in 66% hepatectomized rats. A standard feeding was obtained from animals with hepatic branch vagotomy, and all rats examined received pair food intake. Liver regeneration was evaluated by the hepatocyte mitotic index. When ursodesoxycholic acid 12.5 mg kg(-1) day(-1) was administered orally, a significant increase in the mitotic index was observed 2 and 3 days after hepatectomy, and the mitotic index response 2 days after hepatectomy was dose-dependent in the range of 0-25 mg kg(-1) day(-1). Hepatic branch vagotomy suppressed the mitotic index 2 days after hepatectomy, and the mitotic index increase due to ursodesoxycholic acid was blocked by hepatic branch vagotomy, but not by gastric branch vagotomy. It was also noted that hepatic branch vagotomy or ursodesoxycholic acid or both did not affect serum parameters indicating liver and kidney function. Because ursodesoxycholic acid exists in the bile juice, these results suggest that the hepatic vagus nerve is specifically active with endogenous bile acids in the control of liver regeneration.

Animals↗
PubMed1988

Increased calmodulin synthesis in the pre-replicative phase of rat liver regeneration.

A cytosolic calmodulin wave has been described in the pre-replicative phase of rat liver regeneration. Here we demonstrate that this calmodulin increase is reduced by injection of cycloheximide (translation inhibitor) and actinomycin D (transcription inhibitor). In addition, we found that calmodulin mRNA levels are increased during the early pre-replicative period of liver regeneration, and this increase is affected by actinomycin D. Together, these results strongly indicate that the calmodulin wave observed in the pre-replicative phase of liver regeneration is due to de novo synthesis of this protein.

Animals↗
PubMed2002

Changes in the pool of bile acids in hepatocyte nuclei during rat liver regeneration.

BACKGROUND/AIMS: To investigate changes in nuclear bile acids (BAs) during rat liver regeneration. METHODS: Nuclei were isolated from control rat livers and after two-thirds partial hepatectomy (PH). BAs in bile, liver homogenate and nuclei were measured by gas chromatography-mass spectrometry. Nuclear translocation of radiolabeled BAs was determined using fresh isolated hepatocytes from control donors. RESULTS: Liver BA concentrations were transiently reduced after PH. Relative increases in: -MCA at 1 day, deoxycholic acid at 7 days and cholic acid (CA) at 3 and 14 days were found. Nuclear BAs accounted for <0.5% of liver BAs. Contamination with cytosolic BAs during nuclei isolation was <4%. Unconjugated- and conjugated-CA were able to reach the nucleus with similar efficiency. The pattern of nuclear BAs--CA (80%) and ursodeoxycholic acid (UDCA) (8.5%) being the most abundant--did not match that found in liver or bile. A transient decrease in CA/UDCA ratio, in absence of significant change in total BA content, was observed in nuclei after PH. "Flat" BA species were only detected in homogenate, but not in nuclei, at 1 day after PH. CONCLUSIONS: BA pool in nuclei of rat hepatocytes, whose composition is different to that of total liver BA pool, undergoes important changes during liver regeneration.

Animals↗
PubMed1992

Effect of pancreaticobiliary diversion on liver regeneration.

To ascertain whether the increase in cholecystokinin (CCK) level associated with pancreaticobiliary diversion has a cytoproliferative effect on the liver similar to that on the pancreas, we studied three groups of rats: group I (n = 19) had a pancreaticobiliary diversion and 4 weeks later a 70% liver resection, group II (n = 13) had a liver resection only, and group III (n = 6) underwent a sham liver operation. Tissue samples were taken from the liver and pancreas 48 h after the liver operation. Liver regeneration was evaluated on the basis of continuous incorporation of tritiated thymidine into hepatocytes, liver weight, and DNA content. For confirmation of the increase in CCK levels the effects on the pancreas was studied by measuring wet weight, total protein, and total DNA content. The results showed trophic effects on the pancreas, as expected, but no effects whatsoever on liver regeneration. CCK does not seem to have any role in the regulation of liver regeneration.

Animals↗
PubMed1983

Enzymic retrodifferentiation during hepatocarcinogenesis and liver regeneration in rats in vivo.

The work presented here has concerned the study of early, as well as late, enzymic changes occurring during diethylnitrosamine-induced hepatocarcinogenesis and liver regeneration after partial hepatectomy in comparison with normal liver differentiation. Rank correlation analysis of the enzyme data suggested a step-wise retrodifferentiation i.e. that the liver during carcinogenesis first assumed a neonatal enzymic pattern before attaining a foetal enzymic state. Similar enzymic changes were observed in regenerating liver after partial hepatectomy; again there was a step-wise retrodifferentiation of enzymic pattern and at 3 days post hepatectomy the liver had an enzymic pattern similar to both foetal and neoplastic liver. However, in contrast to liver undergoing neoplastic change, the regenerating liver retained the capacity to undergo redifferentiation towards a normal adult biochemical pattern.

Animals↗