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PubMed2000

Comparison of iceball diameter and temperature distribution achieved with 3-mm accuprobe cryoprobes in porcine and human liver tissue and human colorectal liver metastases in vitro.

We aimed to assess the thermal profile and size of iceballs produced by Accuprobe cryoprobes in fresh porcine and human liver and human colorectal cancer liver metastases in vitro to allow better planning of cryosurgical treatment of liver metastases. Iceballs were produced by a 20-min single freeze cycle using 8-mm cryoprobes in pig liver in a waterbath at 37 degrees C (n = 8) and 3-mm cryoprobes in pig liver (n = 8), human liver (n = 3), and human colorectal cancer liver metastases (n = 8). The iceball diameters and the temperatures at different distances from the cryoprobe were measured. Mean iceball diameters produced by 8-mm cryoprobes in pig liver were 56.3 mm and varied from 38.7 to 39.6 mm for 3-mm cryoprobes in the different tissues used. There was no significant difference in iceball size in the different tissues. The diameter of the zone of -40 degrees C or less was approximately 44 mm using 8-mm cryoprobes in porcine liver and between 27 and 31 mm using 3-mm cryoprobes in the different tissues examined. The results may allow better preoperative planning of the cryosurgical treatment of liver metastases with Accuprobe cryoprobes.

Animals↗
PubMed1978

The drug metabolism systems of liver and liver tumors: a comparison of activities and characteristics.

Transplantable rat liver tumors 5123 t.c., 7288 ct.c., 5123 t.c.(H) and the Novikoff hepatoma have active mixed function oxidase systems capable of metabolizing a variety of drug and polycyclic hydrocarbon substrates. The tumor drug metabolism systems are at best 20% as active as rat liver. The tumor drug metabolism activities are induced by pretreatment with phenobarbital or beta-naphthoflavone and can be inhibited with specific inhibitors such as carbon monoxide or 7,8-benzoflavone. Tumor drug metabolism systems appear to consist of cytochrome P-450 and cytochrome P-450 reductase. The properties of the two protein components from tumors are highly similar to the corresponding components of the liver drug metabolism system. Cytochrome P-450 reductase has been at least partially purified from the Novikoff hepatoma and hepatoma 5123 t.c.(H). The kinetic and physical properties of the tumor reductases are similar to those of the liver reductase except that the Km of hepatoma 5123 t.c.(H) reductase, but not of the Novikoff hepatoma reductase for NADPH, is elevated an order of magnitude over the Km of the liver reductase. The mechanism for the interaction of electron donor and electron acceptor with liver or tumor reductases seems to be a sequential reaction mechanism. Experiments on the NADP-inhibition of the interaction of NADPH and cytochrome c with liver reductase indicate that NADP is competitive with NADPH and noncompetitive with cytochrome c. This result is consistent with the postulate of a sequential reaction for NADPH-cytochrome P-450 reductases of liver and tumors. These data support the conclusions that an active drug metabolism system is present in liver tumors and that the tumor systems are constituted like the liver system.

Animals↗
PubMed1975

Hepatoma, host liver, and normal rat liver neutral lipids as affected by diet.

Groups of normal and hepatoma (7288CTC) bearing rats were maintained on normal chow and fat-free diets for 4 weeks. Normal liver, host liver, and hepatoma neutral lipids were examined in detail and compared. Water content, unaffected by diet was: hepatoma, 82 percent; host liver, 71 percent; and normal liver, 67 percent. The fat-free diet had no effect upon the hepatoma neutral lipids but elevated the triglyceride level in normal and host liver, shifted the triglyceride carbon number distribution to lower mol wt, and elevated the percentage of monoenoic acids in triglycerides and cholesteryl esters. Host triglyceride concentrations were ca. half, and cholesterol levels were reduced moderately relative to normal liver values. Hepatoma cholesterol levels were higher and triglyceride concentrations lower than normal and host liver values. Hepatoma triglycerides differed dramatically from liver and were characterized by increased concentrations of high mol wt species and a fivefold increase in the percentage of C-20 and C-22 fatty acids. The percentage of C-20 and C-22 fatty acids in hepatoma cholesteryl esters also increased ca. fivefold relative to liver. The data indicate that the systems that regulate triglyceride and cholesteryl ester fatty acid composition in liver do not control the compositions of these lipid classes in this hepatoma. The unchanged high level of essential fatty acids in the hepatoma lipids from the fat-free fed animals demonstrates the hepatoma's ability to absorb and conserve specific fatty acids.

Animals↗
PubMedDate not supplied

In vitro metabolism of GV150013X by using liver microsomes and liver tissue slices from different species.

The metabolism of GV150013X was studied in vitro using washed liver microsomes and liver tissue slices from different species. This work was carried out in order to compare the metabolite profiles resulting from incubation of GV150013X with human, rat, dog and rabbit liver microsomes and those from rat, rabbit and human liver tissue slices. This compound was found to be converted to at least 8 metabolites by rat and human liver microsomes. In rabbit liver microsomes, the three metabolites M4, M7 and M8, and in dog liver microsomes metabolite M1, were not detected. The main metabolites, M2, M5 and M6, were present in human, rat and rabbit liver tissue slices, while the three metabolites M3, M4 and M8 and metabolite M1 were not detected in rabbit and rat liver tissue slices, respectively. In rat liver tissue slices, the major metabolites plus five minor metabolites, one sulphate conjugate of a monohydroxylated, three trihydroxylated and one dihydroxylated were identified based on HPLC retention time and thermospray-mass spectrometry data. Quantitative species differences among rat, dog, rabbit and human were observed, while qualitative differences only between rabbit and other species were detected.

Adamantane↗
PubMed1999

[Extracorporeal liver assist devices in acute liver failure].

The acute liver failure (ALF) is a complex syndrome resulting from loss of synthetic and metabolic functions of the liver. Despite recent advances in intensive care medicine patients with severe ALF have a very high mortality and the orthotopic liver transplantation still remains the only proven effective treatment of ALF. Numerous attempts have been made to improve survival by using various extracorporeal support techniques, but none of these therapeutic approaches was able to increase the survival rate. Liver support systems based on detoxification procedures only could not influence the deleterious course of the disease. It is certain that an ideal liver support system should be capable to fulfil the liver's essential synthetic and metabolic functions as well as detoxification and excretion. Over the last years the development of hybrid liver assist devices has aimed at replacing these liver functions and therefore might give an advantage over earlier systems based on detoxification techniques only. This article gives a short review of the various liver support systems and focuses then on the hybrid liver support systems, their construction and the remaining problems after the first clinical applications.

Critical Care↗
PubMed2001

A comparison of the costs and effects of liver transplantation for acute and for chronic liver failure.

Little is known about costs and cost-effectiveness of liver transplantation (LTx) for acute liver failure compared to costs and cost-effectiveness of LTx for chronic liver failure. In this study, costs of acute and of chronic LTx patients were determined in a retrospective study. Files of 100 consecutive patients who underwent LTx in 1993-1997 were studied. Costs up to 1 year after LTx were Euro 107,675 (chronic liver failure) and Euro 90,792 (acute liver failure). The difference was mainly caused by higher hospitalisation costs and higher personnel costs for chronic liver failure. Medication costs for acute liver failure were higher, due to a high administration rate of expensive anti-HBs immunoglobulin therapy in patients with viral hepatitis B. LTx for chronic liver failure is more costly and seems to be more cost-effective than LTx for acute liver failure, since 1-year survival is higher in patients who underwent transplantation for chronic liver failure.

Acute Disease↗
PubMedDate not supplied

Liver tumors in fatty liver: difficulty in ultrasonographic interpretation.

BACKGROUND: Fatty liver and liver tumors are very frequent diseases. Sonography (US) currently is the initial diagnostic tool for hepatic exploration. However, there is a marked paucity of US findings of tumors in fatty liver. METHODS: We studied the US findings of 41 lesions (31 patients) with this combination, with special attention paid to internal echoes, marginal echoes, and especially the mode of back echoes, and compared them with the US results of 64 lesions (38 patients) without fatty liver. RESULTS: Comparing the group having liver tumor without fatty liver with the group having liver tumor with fatty liver showed that (a) the number of hypoechoic lesions increased (29 of 41, 70.7%, vs. 16 of 64, 25.0.%), (2) the tumor margin appeared indistinct (32 of 41, 78.0%, vs. nine of 64, 14.1%), and (c) the lesions showing posterior echo enhancement increased (34 of 41, 82.9%, vs. eight of 64, 12.5%). CONCLUSION: Liver tumors in fatty liver are expected to show unusual patterns on US, so we should consider this difficulty when interpreting these US findings and we should not make a conclusion without including other imaging modalities.

Adult↗
PubMed1995

Polyamine metabolism in the rat liver after orthotopic liver transplantation.

We examined the polyamine metabolism in liver transplanted after cold ischemia and effects of putrescine administration on liver injury, liver regeneration, and survival rate after orthotopic liver transplantation in the rat. Male Wistar rats were used as donors and recipients. Grafts were stored in Euro-Collins solution for 6 h at 4 degrees C. Orthotopic liver transplantation was performed by the three cuff technique. The activities of aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase elevated and peaked 4 h after liver transplantation. Hepatic ornithine decarboxylase and spermidine/spermine N1-acetyltransferase activities were also elevated and peaked 8 h after the operation. In agreement with the increases in ornithine decarboxylase and spermidine/spermine N1-acetyltransferase activities, the putrescine content increased and spermidine content decreased in the transplanted liver. Putrescine administrated intraperitoneally improved the survival rate, decreased serum transaminase level and increased the [3H]thymidine incorporation into the liver DNA. These findings suggest that both biosynthetic and biodegradative pathways are stimulated in liver transplantation, resulting in the increase in the formation of putrescine from ornithine and from spermidine, and that putrescine administration improve the survival rate by protecting the damaged graft after cold ischemia and reperfusion and by stimulating liver regeneration.

Acetyltransferases↗
PubMed2005

Expression of osteoactivin in rat and human liver and isolated rat liver cells.

BACKGROUND/AIMS: The transmembrane glycoprotein osteoactivin is expressed in osteoblasts, dendritic cells and tumor cells. It is suggested to influence osteoblast maturation, cell adhesion and migration. We studied osteoactivin expression within the liver. METHODS: Expression of osteoactivin was analysed by RT-PCR, Northern blotting, in situ hybridisation (ISH) and immunohistochemistry (IHC) comparing normal and acutely injured rat liver [induced by carbon tetrachloride (CCl(4)) administration], liver cell populations, and normal or diseased human liver. RESULTS: By ISH osteoactivin expression was detected in sinusoid-lining cells found by IHC to be positive for the common mononuclear phagocyte marker antibody anti-CD68. While total liver contained only traces, isolated Kupffer cells expressed abundant amounts of osteoactivin mRNA further increasing during culture. In acutely injured rat liver osteoactivin expression was strongly increased reaching maximum of expression 48h after CCl(4). By ISH osteoactivin expression was localised in pericentral inflammatory cells and sinusoid-lining cells again anti-CD68 positive. Dexamethasone and lipopolysaccharide decreased osteoactivin expression in cultured mononuclear phagocytes of normal as well as of acutely injured liver. In human liver osteoactivin was increased in fulminant hepatitis and paracetamol intoxication. CONCLUSIONS: Osteoactivin is expressed at high levels in normal and inflammatory liver macrophages suggesting a significant role in acute liver injury.

Acute Disease↗
PubMed2005

Compensatory recovery of liver mass by Akt-mediated hepatocellular hypertrophy in liver-specific STAT3-deficient mice.

BACKGROUND/AIMS: Liver regeneration following hepatectomy is complicated and involves a variety of interacting factors. The present study was designed to study the roles of proliferation and hypertrophy of hepatocytes in liver regeneration following hepatectomy in liver-specific STAT3-knockout (LS3-KO) mice lacking mitogenic activity. METHODS: Partial hepatectomy was performed in LS3-KO and control mice. Liver regeneration was estimated by the liver weight, cell proliferation and cell size, and the related cellular signals were analyzed. RESULTS: Proliferation of hepatocytes following PH was markedly suppressed in LS3-KO mice with reduced cyclinD1 transcript. However, liver mass recovered sufficiently following PH in LS3-KO mice almost equal to that of control mice. Analysis of hepatocellular growth revealed that cell size following hepatectomy was significantly larger in LS3-KO mice than in control mice. Hepatectomy induced immediate but transient phosphorylation of Akt, p70S6K, mTOR and GSK-3beta in LS3-KO mice much more than in control mice. Additionally, adenoviral transfection of dominant negative mutant of Akt to control and LS3-KO mice led to insufficient liver regeneration following hepatectomy. CONCLUSIONS: PI3-K/Akt-mediated responsive hepatocellular hypertrophy may be essential for liver regeneration following hepatectomy and sufficiently compensated liver regeneration even in STAT3-deficient liver, in which cell proliferation is impaired.

Animals↗
PubMed2004

The survival and value of liver transplantation for liver carcinoma: a single-center experience.

UNLABELLED: Liver transplantation for liver carcinoma with cirrhosis is a treatment still in dispute. The objectives were to summarize the survival and cost of 50 liver transplant cases performed for liver carcinoma over nearly 3 years. METHODS: We performed 138 liver transplants from January 1999 to February 2002. There were 50 cases (36.2%) of liver carcinoma with HBV cirrhosis, which were divided into three stages based on the tumor pathology: Stage 1 cases showed a single mass (< or = 5 cm), 4 cases; Stage 2, a single mass > 5 cm or intrahepatic multiple masses without PV cancer embolus, 32 cases; and Stage 3: tumor invasion of the PV or perihepatic lymph nodes or organs, 14 cases. All patients received three to six courses of chemotherapy postoperatively. RESULTS: All four cases of stage 1 survived > 1 year; one of them is at 3 years with good liver function and tumor free. The mean half-year medical cost was $27.100 +/- 108 in stage 1. The half-year survival and medical costs were 62.5% and $31,500 +/- 260 in stage 2 and 15.0% and $35,500 +/- 134 in stage 3. CONCLUSION: Liver transplantation is an effective treatment for early-stage liver carcinoma, that achieves good medical and economic results, but should be limited to advanced liver cancer.

Analysis of Variance↗
PubMed2001

Eotaxin expression and eosinophil infiltrate in the liver of patients with drug-induced liver disease.

BACKGROUND: Drug-induced liver disease is due to intrinsic or idiosyncratic hepatotoxins. Liver parenchyma is then infiltrated by immunocompetent cells. Eosinophils are primarily tissue leukocytes which are attracted into tissues by various chemoattractants, including chemokines. The aim of this study was to study eosinophils in the livers of patients with drug-induced liver disease. METHODS: Immunohistochemical studies with antibodies against eosinophil cationic proteins (major basic protein, eosinophil-derived neurotoxin and eosinophil cationic protein), cytokines (interleukin 5 (IL-5), interleukin 3 (IL-3) and granulocyte-macrophage colony stimulating factor (GM-CSF)) and chemokines (eotaxin and RANTES (Regulated upon Activation Normal T cell Expressed and Secreted)) were performed to assess the in situ activation of the liver-infiltrating eosinophils of 14 patients with drug-induced liver disease and 19 controls. RESULTS: Eosinophils were only observed in patients with drug-induced liver disease. Eosinophils were morphologically normal when hepatitis was due to paracetamol whereas eosinophils had granular changes when hepatitis was due to an idiosyncratic hepatotoxin. Eotaxin was detected in all patients with drug-induced liver disease, whereas RANTES was detected in three of them. IL-5, IL-3 or GM-CSF were not detected. CONCLUSIONS: In patients with drug-induced liver disease, the recruitment of eosinophils in the liver may depend on eotaxin expression. Eosinophil changes may vary according to the type of drug.

Acetaminophen↗
PubMed1994

Liver transplantation for end-stage liver disease associated with alpha-1-antitrypsin deficiency in children: pretransplant natural history, timing and results of transplantation.

Alpha-1-antitrypsin deficiency is an inborn metabolism error which can cause emphysema and liver disease. As regards the pathophysiology of liver disease, this deficiency is poorly understood, and it is also not known why only a small proportion of Pi ZZ individuals progress towards cirrhosis and liver failure. Since there is no specific therapy for end-stage liver disease associated with alpha-1-antitrypsin deficiency, patients are considered candidates for liver transplantation. In this paper, the natural history of 16 children who underwent liver transplantation is reviewed. Fourteen patients had neonatal cholestasis as a first symptom of the disease and hepatosplenomegaly was present in all children by the age of 12 months. In 11 children, jaundice recurred, always with liver function deterioration. Two patients had a histological paucity of interlobular bile ducts and required early transplantation due to rapid progression of liver failure. At the time of pretransplant assessment, all the patients in this study had portal hypertension and seven of them had experienced at least one episode of gastrointestinal bleeding. One child had moderate intrapulmonary shunts with hypoxemia, but the others had normal spirometry and blood gases. There was no other extrahepatic complication of alpha-1-antitrypsin deficiency. Eighteen orthotopic liver transplantations were performed in 16 patients. One patient died 8 days after retransplantation due to graft necrosis. Fifteen patients (94%) were alive after a median follow-up of 22 months with an excellent quality of life, normal serum alpha-1-antitrypsin levels and without evidence of liver disease recurrence or pulmonary complications.(ABSTRACT TRUNCATED AT 250 WORDS)

Child↗
PubMed2000

Partial purification of a liver-derived tumor cell growth inhibitor that differentially inhibits poorly-liver metastasizing cell lines: identification as an active subunit of arginase.

Organ specific tumor metastasis is thought in part to require the ability of metastatic cells to respond to target-organ-associated growth factors or to avoid the effects of target organ associated growth inhibitors. We previously found that murine and rat liver-conditioned media inhibited the growth of the poorly-liver metastasizing murine RAW117-P large-cell lymphoma cells more than their highly liver-metastasizing RAW117-H10 counterparts. Using a six step chromatographic procedure, the major RAW117-P cell proliferation inhibitor from a rat liver extract was purified. The factor displayed a Mr of approximately 35,000 and an isoelectric point > 8.5. This material inhibited the growth of many cells at high concentration; however, in dose-response studies it displayed a higher IC50 for highly-liver metastatic murine RAW117-H10 lymphoma and human KM12SM colon carcinoma cells than for their poorly-liver metastatic counterparts. Attempts to identify the growth inhibitor led to the supplementation of tissue culture inhibitor assays with various components, including excess amino acids, and this was found to completely abrogate the factor's activity. Specifically, the addition of excess arginine resulted in the complete cellular recovery from inhibitor exposure. This tentatively identified the liver growth inhibitor as the enzyme arginase, a Mr approximately 10,000 multisubunit protein. A microtiter plate-based assay for arginase was developed and the purification repeated using human liver as a source of activity and the human KM12C colon carcinoma line as a target. The growth inhibitory and arginase activities were found to co-purify, identifying the factor as arginase. Highly-metastatic cells displayed no ability to preferentially inactivate or inhibit the activity of arginase, but they did they display slightly greater amounts of intracellular arginine. The liver is a major site of arginase localization as the enzyme is required for the functioning of the urea cycle. The results indicate that certain liver-colonizing tumor cells can escape, to a degree, the proliferation-damping effects of arginine depletion.

Animals↗
PubMed1986

Mitochondrial damage and the subcellular distribution of 2-oxoglutarate:glyoxylate carboligase in normal human and rat liver and in the liver of a patient with primary hyperoxaluria type I.

The subcellular distribution of 2-oxoglutarate:glyoxylate carboligase was investigated in a normal human liver, a liver from a patient with pyridoxine-resistant primary hyperoxaluria type I and rat livers subjected to various degrees and types of trauma. On continuous sucrose gradients most of the carboligase fractionated with a peak equilibrium density of 1.19-1.20 g/cm3 and paralleled the distribution of the major peaks of monoamine oxidase, glutamate dehydrogenase and cytochrome oxidase and can be considered to be mitochondrial. Various proportions of the carboligase and mitochondrial marker enzymes were found to be 'extramitochondrial' (at or near the top of the sucrose gradients), depending on the liver source and the severity of trauma to which they were subjected. Carboligase, monoamine oxidase (outer membrane marker) and glutamate dehydrogenase (matrix marker) were released from mitochondria by the homogenization and centrifugation procedures, to the extent of 19.9%, 32.4% and 11.5% respectively in hyperoxaluric liver, 12.5%, 17.9% and 8.2% in normal human liver and 3.0%, 4.9% and 3.8% in control rat liver. The proportion of extramitochondrial cytochrome oxidase (inner membrane marker) was virtually undetectable in both human and rat livers. However, sonication of rat liver homogenates or the addition of the detergent Triton X-100 caused a massive release of all four enzymes. The extramitochondrial carboligase was probably in the form of a free protein of very high molecular weight or aggregate, rather than associated with a mitochondrion-derived organelle. Subfractionation of a rat liver mitochondrial preparation indicated that most of the carboligase activity paralleled activities of 2-oxoglutarate decarboxylase, citrate synthase and glutamate dehydrogenase and was probably located in the matrix.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2001

Effects of prostaglandin E(1) on the efficacy of xenogeneic extracorporeal pig liver perfusion in a canine model of acute liver failure.

Xenogeneic extracorporeal liver perfusion (ECLP) has the potential to become an important tool in the management of patients with severe liver failure. We previously showed that xenogeneic pig liver perfusion may be prolonged for up to 9 hours by the administration of prostaglandin E(1) (PGE(1)). In this study, we used a canine model of acute liver failure to evaluate the effects of PGE(1) on the efficacy of ECLP as a liver-assist device. Liver failure was surgically induced in 12 beagle dogs, with a control group (group 1, n = 4) not connected to the ECLP circuit. Direct cross-circulation between the dogs and the ECLP circuit using a pig liver was performed without (group 2, n = 4) or with (group 3, n = 4) continuous administration of PGE(1) through the portal vein of the pig liver. The duration of cross-circulation in group 3 (9.4 +/- 1.2 hours) was significantly longer than in group 2 (4.3 +/- 1.0 hours). In addition, elevation of blood ammonia, total bile acid, and hyaluronic acid levels was less marked in group 3 compared with the other 2 groups. The ratio of branched-chain amino acids to aromatic amino acids was also improved in group 3. The mean survival time in group 3 (26.6 +/- 0.4 hours) was significantly longer than in group 1 (15.5 +/- 1.3 hours) or group 2 (17.1 +/- 2.9 hours). Continuous administration of PGE(1) to xenogeneic ECLP resulted in a significant improvement in both liver function and survival time of dogs with surgically induced liver failure.

Alprostadil↗
PubMed1996

Pharmacokinetics and pharmacodynamics of cisatracurium in patients with end-stage liver disease undergoing liver transplantation.

We determined the pharmacokinetics and pharmacodynamics of cisatracurium, one of the 10 isomers of atracurium, in 14 patients with end-stage liver disease undergoing liver transplantation and in 11 control patients with normal hepatic and renal function undergoing elective surgery. Blood samples were collected for 8 h after i.v. bolus administration of cisatracurium 0.1 mg kg-1 (2 x ED95). Plasma concentrations of cisatracurium and its metabolites were determined using an HPLC method with fluorescence detection. Pharmacokinetic variables were determined using non-compartmental methods. Neuromuscular block was assessed by measuring the electromyographic evoked response of the adductor pollicis muscle to train-of-four stimulation of the ulnar nerve using a Puritan-Bennett Datex (Helsinki, Finland) monitor. Pharmacodynamic modelling was completed using semi-parametric effect-compartment analysis. Volume of distribution at steady state was 195 (SD 38) ml kg-1 in liver transplant patients and 161 (23) ml kg-1 in control patients (P < 0.05), plasma clearance was 6.6 (1.1) ml kg-1 min-1 in liver transplant patients and 5.7 (0.8) ml kg-1 min-1 in control patients (P < 0.05), but elimination half-lives were similar: 24.4 (2.9) min in liver transplant patients vs 23.5 (3.5) min in control patients (ns). The time to maximum block was 2.4 (0.8) min in liver transplant patients compared with 3.3 (1.0) min in control patients (P < 0.05), but the clinical effective duration of action (time to 25% recovery) was similar: 53.5 (11.9) min in liver transplant patients compared with 46.9 (6.9) min in control patients (ns). The recovery index (25-75% recovery) was also similar in both groups: 15.4 (4.2) min in liver transplant patients and 12.8 (1.9) min in control patients (ns). After cisatracurium, peak laudanosine concentrations were 16 (5) and 21 (5) ng ml-1 in liver transplant and control patients, respectively. In summary, minor differences in the pharmacokinetics and pharmacodynamics of cisatracurium in liver transplant and control patients were not associated with any clinically significant differences in recovery profiles after a single dose of cisatracurium.

Adult↗
PubMed2006

Hepatocyte proliferation during liver regeneration is impaired in mice with liver-specific IGF-1R knockout.

Recent evidence indicates that growth hormone (GH) is involved in liver regeneration. To test whether insulin-like growth factor I (IGF-I) mediates this effect, we studied liver regeneration induced by partial hepatectomy in liver-specific IGF type 1 receptor knockout (LIGFREKO) mice. The absence of IGF-1R caused a significant decrease in hepatocyte proliferation in males (-52%), but not in females, as assessed by Ki67 immunohistochemistry. Cyclin D1 and cyclin A protein levels in the livers of LIGFREKO males were only half those in controls, indicating that cyclin induction during liver regeneration is dependent on IGF-1R signaling. Analyzing the signaling cascade initiated by IGF-1R, we observed a lack of IRS-1 induction in LIGFREKO livers. In contrast, the induction of IRS-2 synthesis was similar in LIGFREKO and control groups, suggesting the existence of differential regulation of IRS synthesis during liver regeneration. Regenerating livers from LIGFREKO animals also showed significantly less activated ERKs than controls. Our findings demonstrate that IGF-1R makes a significant contribution to liver regeneration. Using the LIGFREKO model, we provide new evidence that IGF-1R/IRS-1/ERK signaling may be the intracellular pathway controlling the cell cycle via cyclin D1 and cyclin A in the regenerating liver.

Animals↗