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PubMedDate not supplied

Liver regeneration after hepatectomy.

Following hepatectomy, liver "knows" when to start and when to stop growing, and thereby accurately regulates its mass. Partial hepatectomy triggers hepatocyte proliferation whereas excessive liver mass (transplant) is regulated by apoptosis. Liver regeneration mainly involves the activation of adult hepatocytes and possibly of liver precursor ("stem") cells. The multistep process of liver regeneration comprises at least 2 critical phases: the transition of the quiescent hepatocyte into the cell cycle (priming) and the progression beyond the restriction point in the G1 phase of the cycle. The priming phase is characterized by the expression of immediate early genes. Activation of protooncogenes in the immediate early gene response involves both transcriptional and post-transcriptional mechanisms. Activation of four transcription factors, NF kappa B, STAT3, AP-1, and C/EBP beta, causes secondary activation of multiple genes and plays an important role in the initiation of hepatic regeneration. The passage of primed hepatocytes through the cell cycle is characterized by the expression of cell cycle genes and requires growth factors. An equilibrium between stimulator and inhibitor genes of the cell cycle expressed after hepatectomy, may explain why the liver regeneration is a tightly regulated growth process. Based on the knowledge of the regulation of liver regeneration, several practical considerations and potential therapeutic strategies can be applied in humans with hepatic dysfunction due to liver resection.

Animals↗
PubMed1999

Transcriptional regulatory signals define cytokine-dependent and -independent pathways in liver regeneration.

Partial hepatectomy and toxic liver damage induce signals in the liver that result in rapid changes in the transcriptional milieu, including activation of latent transcription factors NF-kappa B and STAT3, and induction of expression of early growth response genes. Several of these changes within hepatocytes, including STAT3 and NF-kappa B induction are dependent on the cytokines, TNF alpha and interleukin-6 (IL-6), that are presumably released from non-parenchymal liver cells within minutes of the hepatectomy. IL-6 is a critical factor in the mitogenic response during liver regeneration and is important for both cell cycle progression and protection from liver injury. However, it is not a complete factor in that it is responsible for only a subset of the gene expression changes that occur after hepatectomy and is insufficient alone to cause hepatic DNA synthesis. C/EBP beta, a leucine zipper transcription factor, acts in an IL-6 independent fashion to induce a separate set of genes and proteins and is also required for normal liver regeneration. Moreover, some early growth response genes such as PRL-1, which encodes a nuclear protein tyrosine phosphatase, are induced normally in the absence of C/EBP beta and IL-6 and highlight the role of other transcriptional complexes such as Egr-1 in the early phases of liver regeneration. Thus, cytokine-dependent and -independent pathways act cooperatively to control the complex series of events that result in liver regeneration. The requirement for multiple signals also protects the liver from undergoing hyperplasia in the absence of a compensatory need.

Animals↗
PubMed1995

Cytokines, nitric oxide synthesis and liver regeneration.

During the prereplicative period of liver regeneration the changes in the levels of mRNA for tumour necrosis factor-alpha (TNF-alpha) and its receptors were nearly synchronous. The mRNA levels reached their maximum 1-3 h after operation and exceeded the values for intact animals about ten-fold. Lipopolysaccharide stimulation induced an increase in TNF-alpha and TNF receptor production comparable with that occurring during regeneration. Nitric oxide (NO) production in the regenerating liver was determined by electron paramagnetic resonance (EPR) spectroscopy. The first increase in NO production occurred approximately 1 h after partial hepatectomy (PHE). The second and more pronounced peak of NO production was observed about 6 h after PHE when the hepatocytes entered the first cell cycle; it originated mainly from these cells. The consequent minimum of NO synthesis coincided with the maximal rate of DNA synthesis. The third gradual rise of NO production was seen at the transit from the first to the second cell cycle of the hepatocytes and the entrance of the non-parenchymal cells into proliferation. Hepatocytes, Kupffer and endothelial cells were isolated from livers after PHE. They were found to start their main NO production in the described sequence at the times corresponding to their respective entrance into the cell cycle. The maxima of NO synthesis were inversely correlated to the DNA-synthesizing activity of the individual cell type.

Animals↗
PubMed1983

alpha-Fetoprotein and albumin mRNA levels in liver regeneration and carcinogenesis.

Using a titration procedure, we measured the proportion of alpha-fetoprotein (AFP) and albumin mRNA in normal, regenerating, and preneoplastic rat livers. AFP mRNA constitutes approximately 0.006% of the polysomal polyadenylated RNA of normal livers and this proportion increases only slightly before the onset of DNA synthesis in liver regeneration induced by partial hepatectomy or CCl4 injury. In either model of liver regeneration, the proportion of AFP mRNA in polysomal RNA is highest approximately 24 h after the peak of DNA synthesis. The increase in the proportion of AFP mRNA in polysomal RNA is relatively small during liver regeneration (2-4-fold) but is larger (30-50-fold) in preneoplastic livers of rats fed a choline-deficient diet containing 0.1% ethionine. In contrast to those changes in AFP mRNA, albumin mRNA levels remain unchanged during liver regeneration and double in preneoplastic livers. Our results indicate that the concept of "retrodifferentiation" as it applies to liver regeneration and certain types of hepatic neoplasia needs reevaluation.

Albumins↗
PubMed1994

Regulating factors of liver regeneration after hepatectomy.

The factors regulating liver regeneration were studied by measuring changes in the liver volume and serum hepatocyte growth factor (HGF) levels after hepatectomy. Changes in the liver volumes were studied in 68 hepatectomized patients, including (A) hepatoma patients who had chronic hepatitis or liver cirrhosis (n = 44) and (B) metastatic liver cancer patients who had normal liver parenchyma (n = 24). The hepatic volume increased by 13.8% of the remnant hepatic volume in group A and by 49.1% in group B. The examined factors included the percentage of resected liver volume (%RLV) and the results of laboratory tests. Regression analysis showed that in group A, both %RLV (beta = 0.46) and the serum total bilirubin (T-Bil) level (beta = -0.33) correlated significantly with the extent of liver regeneration and that in group B, only %RLV (beta = 0.78) correlated significantly with the regeneration. Serum HGF levels after hepatectomy were studied in 21 hepatectomized patients, including 11 hepatoma patients and 10 patients with some types of metastatic liver cancer. Serum HGF levels increased significantly after surgery in all 21 patients. Regression analysis, however, showed that the change in HGF was related to liver cirrhosis (beta = 0.46) and to the maximal postoperative T-Bil level (beta = 0.51) but not to the extent of liver regeneration after hepatectomy. These results suggest that liver regeneration is regulated primarily by factors relating to the percentage of the resected liver parenchyma and that serum HGF levels do not directly relate to liver regeneration after surgery.

Aged↗
PubMed2001

Immunotherapy directed against alpha-fetoprotein results in autoimmune liver disease during liver regeneration in mice.

BACKGROUND & AIMS: Priming immune responses against alpha-fetoprotein (AFP) highly expressed in the majority of hepatocellular carcinomas results in significant antitumoral T-cell responses. Liver regeneration in humans and mice, however, is also associated with increased AFP expression. Therefore, we evaluated the risk of AFP-directed immunotherapeutic approaches to induce autoimmunity against the regenerating liver. METHODS: Mice were immunized with DNA encoding mouse AFP. For induction of liver regeneration, partial hepatectomy was performed and mice were monitored by serial histopathologic examinations and measurements of serum ALT activities (U/L), and by determination of the kinetics of AFP-specific T-cell responses. RESULTS: Livers of AFP immune mice without partial hepatectomy were characterized by minor lymphocytic infiltrations without transaminase elevations. By contrast, a significant hepatocyte damage was observed in regenerating liver that correlated well with the number of AFP-specific CD8(+) T cells, the activity of liver regeneration, and the level of AFP synthesis. Autoimmune liver damage was mediated by CD4(+) T cell-dependent CD8(+) cytotoxic T lymphocytes. CONCLUSIONS: These results show that priming of T-cell responses against shared tumor-specific self antigens may be accompanied by induction of autoimmunity dependent on the level of expression of the self antigen and have important implications for the development of antitumoral vaccines targeted against antigens that are not strictly tumor-specific.

Animals↗
PubMed2000

Expression and activation of pro-MMP-2 and pro-MMP-9 during rat liver regeneration.

Partial hepatectomy triggers a variety of biological phenomena, which culminate in regeneration of the liver mass. Hepatocyte proliferation is a major feature of the regenerating liver after partial hepatectomy. Previous studies in our laboratory suggested that hepatic matrix remodeling might be a prerequisite process for hepatocyte proliferation in the regenerating liver. In the present study we use immunohistochemical staining, Western blot analysis, and gelatin zymography to show that the inactive matrix metalloproteinases (MMPs), pro-MMP-2 and pro-MMP-9, are elevated at 30 minutes and activated at 6 to 12 hours and at 3 to 6 hours, respectively, after hepatectomy. Sham-operated livers did not show an increase in inactive pro-MMP-2 and pro-MMP-9 and did not contain active MMP-2 or MMP-9. To examine whether tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) is changed to regulate the activities of MMPs after partial hepatectomy, the level of TIMP-1 protein was analyzed by both immunohistochemistry and Western blot analysis. The level of TIMP-1 protein appears to increase by 6 to 18 hours, implying that an increase in TIMP-1 regulates activities of active MMP-2 and MMP-9. Taken together, these results suggest that hepatic matrix remodeling is mediated by activated MMPs, which contribute to modulation of the environment surrounding hepatocytes during rat liver regeneration.

Animals↗
PubMed2003

Plasminogen mediates liver regeneration and angiogenesis after experimental partial hepatectomy.

BACKGROUND: Plasmin system components are upregulated after partial hepatectomy, but their contribution to surgery-induced hepatic angiogenesis and regeneration is unclear. Liver regeneration and angiogenesis after partial hepatectomy were examined in mice lacking plasminogen or urokinase plasminogen activator (uPA). METHODS: Mice with a single-gene deletion of plasminogen or uPA were subjected to 70 per cent partial hepatectomy. Liver regeneration was measured as relative liver weight and cell proliferation index. Angiogenesis was quantified by determining hepatic microvessel density after staining for sinusoidal endothelial cells. RESULTS: The liver remnant weight was significantly reduced in mice lacking plasminogen or uPA compared with that in wild-type mice on days 2 and 7 after partial hepatectomy. This correlated with impaired cell proliferation. In wild-type mice, regeneration was accompanied by a significant increase in microvessel density after hepatectomy; this increase was impaired in plasminogen-deficient mice. CONCLUSION: Plasminogen and uPA are essential for optimal liver regeneration. In addition, plasminogen appears to be a major determinant in regeneration-associated hepatic angiogenesis.

Animals↗
PubMed2004

Uncoupling protein-2 deficiency promotes oxidant stress and delays liver regeneration in mice.

The control of liver regeneration remains elusive. Because reactive oxygen species (ROS) are able to mediate cell growth arrest and activate proteins that inhibit the cell cycle, ROS production may have a negative impact on liver regeneration. We examined how liver regeneration is affected by uncoupling protein-2 (UCP2), an inner mitochondrial membrane carrier that senses and negatively regulates superoxide production. Liver regeneration was monitored up to 5 days and was found to be significantly delayed in UCP2(-/-) mice after partial hepatectomy. Apoptosis rates in UCP2(+/+) and UCP2(- /-) liver remnants were similar, while parameters of cell proliferation indicated a diminished response in UCP2(- /-) mice with corresponding changes in the expression of key cell cycle regulatory proteins and prolonged activation of stress-responsive protein kinase p38. Levels of malondialdehyde, a marker of ROS generation and oxidant stress, were elevated in UCP2(- /-) livers at every examined time point. Liver remnants of UCP2(+ /+) mice 48 hours post-hepatectomy showed a fourfold increase in the expression of UCP2 protein primarily detected in hepatocytes. In conclusion, our results suggest that absent or insufficient UCP2 function in the regenerating liver results in increased ROS production and negatively modulates the control of cell cycle.

Animals↗
PubMed1987

[Effects of TJN-101, a lignan compound isolated from Schisandra fruits, on liver fibrosis and on liver regeneration after partial hepatectomy in rats with chronic liver injury induced by CCl4].

TJN-101 ((+)-(6S,7S,R-biar)-5,6,7,8-tetrahydro-1,2,3,12-tetramethoxy -6,7-dimethyl-10,11-methylenedioxy-6-dibenzo[a,c]cyclooctenol) is one of the lignan compounds isolated from Schisandra fruits. 1) Effect of TJN-101 on liver fibrosis was investigated in rats which were injected with CCl4 (1 ml/kg) subcutaneously twice a week for 12 weeks. TJN-101 was given orally at the dose of 10 or 30 mg/kg/day for 6 or 3 weeks beginning on the 6th or 9th week after the start of CCl4-intoxication, respectively. The elevations of serum transaminase activities and the increase of liver 4-hydroxyproline content were observed depending on the period of CCl4-intoxication. These changes were marked on the 9th and 12th weeks after. In the histopathological study, the degenerative fatty change on the 6th week after and the formation of pseudolobule caused by fibrosis proliferation on the 9th or 12th week after were mainly observed. When rats were treated with TJN-101, the abnormalities in biochemical parameters and the fibrosis proliferation caused by CCl4-intoxication were improved. 2) Chronic liver injury was induced by the treatment with CCl4 (1 ml/kg) subcutaneously twice a week for 10 weeks to investigate the effect of TJN-101 on liver regeneration after partial hepatectomy. TJN-101, which was given orally at the dose of 10, 30 or 100 mg/kg/day for 6 days from the 1st day after partial hepatectomy, dose-dependently increased the liver regeneration rate and improved the serum BSP retention rate. These results suggest that TJN-101 suppresses the fibrosis proliferation and accelerates both the liver regeneration and the recovery of liver function after partial hepatectomy in chronic liver injury.

Administration, Oral↗
PubMedDate not supplied

Effects of a high-fiber diet on hepatocyte apoptosis and liver regeneration after partial hepatectomy in rats with fatty liver.

BACKGROUND: The morbidity and mortality that accompany fatty liver may occur as a result of increased apoptosis of hepatocytes and decreased liver regeneration. We determined the effects of a high-fiber diet on hepatocyte apoptosis and liver regeneration after partial hepatectomy in rats with fatty liver. METHODS: Fatty liver was induced in male Wistar rats weighing around 200 g through feeding of a high-fat diet for 4 weeks. The rats were then randomly assigned to 3 groups that received a high-fat diet, a normal diet, or a high-fiber diet for another 4 weeks. Partial hepatectomy (around 70%) was performed, and rats were killed 6, 24, 48, or 72 hours after hepatectomy. We then measured (1) the ratio of remnant liver weight to body weight and assessed the histology of the remnant liver as indicators of fatty liver, (2) caspase-3 activity and in situ cell death detection of DNA fragmentation as indicators of apoptosis, and (3) 5-bromo-2-deoxyuridine (BrdU) activity and (4) ornithine decarboxylase (ODC) contents in remnant livers as markers of regeneration. RESULTS: We found that (1) a high-fat diet for 4 weeks can markedly induce fatty liver, (2) apoptosis of hepatocytes is greater in fatty liver than in normal liver (98 +/- 19 vs 36 +/- 7) at 6 hours after partial hepatectomy (p < .05), (3) the capacity of liver regeneration decreases significantly (BrdU index: 30 +/- 5 vs 12 +/- 3, and ODC contents: 604 +/- 48 vs 390 +/- 42 mg/dL) in fatty liver 24 hours after partial hepatectomy (p < .05), (4) a normal diet can partially reverse the effects of fatty liver; (5) a high-fiber diet can significantly reverse the effects of fatty liver (p < .05). CONCLUSIONS: A high-fiber diet can reverse the negative effects of fatty liver on apoptosis and regenerative capacity after partial hepatectomy.

Animals↗
PubMed2001

Mammalian augmenter of liver regeneration protein is a sulfhydryl oxidase.

BACKGROUND: Augmenter of Liver Regeneration is an important secondary hepatic growth factor. Augmenter of liver regeneration protein has been shown to control mitochondrial gene expression and the lytic activity of liver-resident Natural Killer cells through the levels of interferon-gamma, but the precise enzymatic function of this protein is unknown. AIMS: To define the enzymatic activity of augmenter of liver regeneration protein. The carboxy terminus of augmenter of liver regeneration protein contains a special CXXC motif characteristic for redox proteins and with faint homologies to the redox-active site of sulfhydryl oxidases. Tests were, therefore, carried out to establish whether isolated augmenter of liver regeneration protein can also function in the formation of sulfur bridges. METHODS: Purified augmenter of liver regeneration proteins from rat and human were tested in enzyme assays for the ability to introduce disulfide bonds into protein substrates. The isolated proteins were tested for the formation of dimers and the presence of bound FAD was investigated spectroscopically. The function of the conserved CXXC motif was investigated by in vitro mutagenesis experiments and subsequent enzyme assays. RESULTS: In this study, we demonstrate that rat and human augmenter of liver regeneration protein are flavin-linked sulfhydryl oxidases that catalyze the formation of disulfide bonds in reduced protein substrates. A flavin moiety is firmly but not covalently attached to the protein. In human cell cultures augmenter of liver regeneration protein is expressed in a long and short form that both exist as covalently linked dimers. The active site of the enzyme is associated with a conserved CXXC motif in the carboxy-terminal domain, that is present in the homologous proteins from yeast to humans and also in the human Q6 growth regulator protein. In vitro mutagenesis of one cysteine residue in the CXXC motif results in loss of enzymatic function and the mutated protein no longer binds FAD. CONCLUSIONS: For the first time, these data assign an enzymatic activity to the important hepatic growth factor augmenter of liver regeneration protein. The finding that augmenter of liver regeneration protein acts as a FAD-linked sulfhydryl oxidase is essential to identify the molecular targets inside liver cells and to elucidate the precise role of mammalian augmenter of liver regeneration protein in hepatic cell growth, liver disease and regeneration.

Animals↗
PubMedDate not supplied

The effect of chronic ethanol feeding on ornithine decarboxylase activity and liver regeneration.

The effects of ethanol on liver regeneration are poorly understood. Acute and chronic exposure to ethanol have been found to exert opposite effects on the induction of ornithine decarboxylase, the rate-limiting enzyme for polyamine biosynthesis. Polyamines are necessary for DNA synthesis and liver regeneration after chemical or surgical liver injury. Short-term exposure to ethanol, which inhibits ornithine decarboxylase has been shown to inhibit DNA synthesis and liver regeneration, whereas more chronic exposure to ethanol increases ornithine decarboxylase activity and therefore could conceivably stimulate DNA synthesis and regeneration. To explore this later possibility, the effects of chronic ethanol consumption on ornithine decarboxylase activity, DNA synthesis and liver regeneration were studied in rats after sham laparotomy and partial hepatectomy. Chronic ethanol feeding failed to inhibit the induction of ornithine decarboxylase that occurred after partial hepatectomy and yet significantly inhibited posthepatectomy DNA synthesis and restitution of liver mass. These data suggest that the induction of hepatic polyamine biosynthesis is dissociated from DNA synthesis and liver regeneration after chronic consumption of ethanol.

Alcohol Drinking↗
PubMed2003

The role of hepatocytes and oval cells in liver regeneration and repopulation.

The liver has the unique capacity to regulate its growth and mass. In rodents and humans, it grows rapidly after resection of more than 50% of its mass. This growth process, as well as that following acute chemical injury is known as liver regeneration, although growth takes place by compensatory hyperplasia rather than true regeneration. In addition to hepatocytes and non-parenchymal cells, the liver contains intra-hepatic "stem" cells which can generate a transit compartment of precursors named oval cells. Liver regeneration after partial hepatectomy does not involve intra or extra-hepatic (hemopoietic) stem cells but depends on the proliferation of hepatocytes. Transplantation and repopulation experiments have demonstrated that hepatocytes, which are highly differentiated and long-lived cells, have a remarkable capacity for multiple rounds of replication. In this article, we review some aspects of the regulation of hepatocyte proliferation as well as the interrelationships between hepatocytes and oval cells in different liver growth processes. We conclude that in the liver, normally quiescent differentiated cells replicate rapidly after tissue resection, while intra-hepatic precursor cells (oval cells) proliferate and generate lineage only in situations in which hepatocyte proliferation is blocked or delayed. Although bone marrow stem cells can generate oval cells and hepatocytes, transdifferentiation is very rare and inefficient.

Animals↗
PubMed1982

Changes in microsomal membrane microviscosity and phospholipid methyltransferases during rat liver regeneration.

During regeneration of rat liver newly synthesized molecules of drug-metabolizing enzymes, like cytochrome P450, are incorporated into proliferating endoplasmic reticulum (ER). Decreased membrane microviscosity facilitates incorporation of the enzyme-protein molecules into the phospholipid matrix of ER. The microviscosity of membranes is altered by: (1) changed ratios of phospholipid to cholesterol, (2) unsaturation of fatty acids in phospholipids, and (3) methylation of phospholipids. Alterations are known to occur in (1) and (2) in the plasma membrane of proliferating cells. Microviscosity and phospholipid methyltransferases in ER have not been investigated during liver regeneration. Therefore, microviscosity and S-adenosyl-L-methionine (SAM) mediated methylation of phosphatidylethanolamine to phosphatidyl-N-methylethanolamine (PME) and phosphatidylcholine (PC) were measured using microsomal membranes of regenerating rat livers at 6-96 h after partial hepatectomy. In the methylated phospholipids, the proportion of PME increased by 3-9% at 1 microM SAM, and, at 200 microM SAM, the proportion of PC decreased by about 5-10% at 12-24 h. Two phase transitions were observed with microsomal membranes between 20 and 40 degrees C. In synthetic liposomes containing PE, PME and PC, microviscosity decreased when the proportion of PME increased or the proportion of PC decreased. Therefore, alterations in phospholipid methyltransferases and consequent changes in membrane phospholipid methylation may contribute to increased membrane fluidity during cell proliferation and incorporation of drug-metabolizing enzymes into ER.

Animals↗
PubMed2005

Liver regeneration and splenic enlargement in donors after living-donor liver transplantation.

Liver regeneration after donor hepactectomy offers a unique insight into the process of liver regeneration in normal livers. As the liver restores itself, concurrent splenic enlargement occurs. There are many theories about why this phenomenon takes place: some investigators have proposed a relative portal hypertension that leads to splenic congestion or, perhaps, the presence of a common growth factor that induces both the liver and spleen to enlarge. Between the months of June 2001 and May 2004, 112 live donor liver transplants (LDLTs) were performed in Chang Gung Memorial Hospital, Kaohsiung, Taiwan. The total number of donor hepatectomies performed during this period was 113, however, because one of the cases required dual donors. Of our 113 donors, we eventually analyzed the data of 109; 4 patients were lost to follow-up 6 months later and were excluded from our study. The average age of our donor population was 32.32 +/- 8.48 years. The mean liver volume at donation was noted to be 1207.72 +/- 219.95 cm3, and 6 months later, it was 1027.18 +/- 202.41 cm3. Expressed as a percentage of the original volume, the mean liver volume 6 months after hepatectomy was 90.70% +/- 12.47% in this series. For right graft donors, mean liver volume after 6 months was 89.68% +/- 12.37% of the original liver volume, whereas that for left graft donors was 91.99% +/- 12.6%. Only 26 of the 109 (23.85%) donors were able to achieve full regeneration 6 months post-donation. Notably, liver function profiles of all donors were normal when measured 6 months after operation. The average splenic volume at donation as measured by computed tomography (CT) volumetry was 159 +/- 58 cm3, and the splenic volume 6 months post-donation was 213 +/- 85 cm3. There was a mean increment in splenic volume of 35% +/- 28% 6 months after donation. The blood profiles of the donors were monitored; particular attention was given to platelet levels and liver function tests, and these were found to be within normal limits 6 months after operation. Of note, splenic enlargement was significantly greater among right-sided donors than their left-sided counterparts. Greater splenic enlargement was also observed in those donors who achieved full liver regeneration at their evaluation 6 months postoperatively than in those who did not. Although original liver volume was not re-established in most patients 6 months after liver donation, there seemed to have been no untoward effects to the donor. The factors that affect liver regeneration are complex and myriad. Although there is splenic enlargement at 6 months post-donation in donors of LDLT, there are no untoward effects of this enlargement.

Adult↗
PubMed2004

Liver regeneration after adult living donor and deceased donor split-liver transplants.

As the number of living donor (LD) and deceased donor (DD) split-liver transplants (SLTs) have increased over the last 5 years, so too has the interest in liver regeneration after such partial-liver transplants. We looked at liver regeneration, as measured by computed tomography (CT) volumetrics, to see if there were significant differences among LDs, right-lobe LD recipients, and SLT recipients. We measured liver volume at 3 months postoperatively by using CT, and we compared the result to the patient's ideal liver volume (ILV), which was calculated using a standard equation. The study group consisted of 70 adult patients who either had donated their right lobe for LD transplants (n = 24) or had undergone a partial-liver transplant (right-lobe LD transplants, n = 24; right-lobe SLTs, n = 11; left-lobe SLTs, n = 11). DD (vs. LDs) were younger (P < 0.01), were heavier (P = 0.06), and had longer ischemic times (P < 0.01). At 3 months postoperatively, LDs had attained 78.6% of their ILV, less than the percentage for right-lobe LD recipients (103.9%; P = 0.0002), right-lobe SLT recipients (113.6%; P = 0.01), and left-lobe SLT recipients (119.7%; P = 0.0006). When liver size at the third postoperative month was compared with the liver size immediately postoperatively, LDs had a 1.85-fold increase. This was smaller than the increase seen in right-lobe LD recipients (2.08-fold), right-lobe SLT recipients (2.17-fold), and left-lobe SLT recipients (2.52-fold). In conclusion, liver regeneration, as measured by CT volume, seems to be greatest in SLT recipients. LD recipients seem to have greater liver growth than their donors. The reason for this remains unclear.

Adult↗
PubMed2002

STAT3 contributes to the mitogenic response of hepatocytes during liver regeneration.

STAT3 is rapidly induced during liver regeneration in an interleukin 6 (IL-6)-dependent fashion, and IL-6 is required for normal liver regeneration. We wanted to know whether STAT3 was also required for liver regeneration but disruption of the STAT3 gene during embryonic stages causes lethality. Therefore, an albumin promoter-driven Cre-loxP recombination system was used to create a STAT3 deletion in the adult mouse liver to study the role of STAT3 in liver regeneration. After partial hepatectomy, there was virtually no STAT3 RNA or protein induction in Alb(+) STAT3(fl/fl) livers. STAT3 DNA binding activity was also absent in Alb(+) STAT3(fl/fl) livers. Unlike in control livers, STAT1 was activated in STAT3 conditional-mutant livers posthepatectomy. Hepatocyte DNA synthesis at 40 h posthepatectomy in Alb(+) STAT3(fl/fl) livers was reduced to approximately one-third of the control. Alb(+) STAT3(fl/fl) livers had abnormalities in immediate-early gene activation that largely correlated with but were not identical to those seen in IL-6-/- livers. G(1) phase cyclins including cyclins D1 and E had lower expression levels in Alb(+) STAT3(fl/fl) livers, indicating an abnormal G(1) to S phase transition. Therefore, STAT3 accounts for part of the DNA synthetic response of the hepatocytes during liver regeneration, which cannot be compensated for by induction of STAT1. Normal activation of the MAPK pathway in Alb(+) STAT3(fl/fl) livers reinforces the fact that at least part of the effect of IL-6 on hepatocyte proliferation is not mediated by STAT3. This study provides the first in vivo evidence that STAT3 promotes cell cycle progression and cell proliferation under physiological growth conditions.

Animals↗