bluuebunny/crossref_metadata_2025_split huggingface dataset:
Atp–Dependent Canalicular Bile Acid Transport: Another Piece of the Puzzle
Authors: Smith Daniel J. 
Published: March 2007

ABSTRPlCT

The secretion of bile by the liver is primarily determined by the ability of the hepatocyte to transport bile acids into the bile canaliculus. A carrier–mediated process for the transport of taurocholate, the major bile acid in humans and rats, was previously demonstrated in canalicular membrane vesicles from rat liver. This process is driven by an outside–positive membrane potential that is, however, insufficient to explain the large bile acid concentration gradient between the hepatocyte and bile. In this study, we describe an ATP–dependent transport system for taurocholate in inside–out canalicular membrane vesicles from rat liver. The transport system is saturable, temperature–dependent, osmotically sensitive, specifically requires ATP, and does not function in sinusoidal membrane vesicles and right side–out canalicular membrane vesicles. Transport was inhibited by other bile acids but not by substrates for the previously demonstrated ATP–dependent canalicular transport systems for organic cations or nonbile acid organic anions. Defects in ATP–dependent canalicular transport of bile acids may contribute to reduced bile secretion (cholestasis) in various developmental, inheritable, and acquired disorders.
Direct photoaffinity labeling of liver plasma membrane subfractions enriched in sinusoidal and canalicular membranes using [35S]adenosine 5′–O–(thiotriphosphate) ([35S]ATPγS) allows the identification of ATP–binding proteins in these domains. Comparative photoaffinity labeling with [35S]ATPγS and with the photolabile bile salt derivative (7,7–azo–3α,12α–dihydroxy–5β–[3β–H]–cholan–24–oyl)–2′–aminethanesulfonate followed by immunoprecipitation with a monoclonal antibody (Be 9.2) revealed the identity of the ATP–binding and the bile salt–binding canalicular membrane glycoprotein with the apparent Mr
of 110,000 (gp110). The isoelectric point of this glycoprotein was 3.7.
Transport of bile salt was studied in vesicles enriched in canalicular and sinusoidal liver membranes. Incubation of canalicular membrane vesicles with [H] taurocholate in the presence of ATP resulted in an uptake of the bile salt into the vesicles which was sensitive to vanadate. ATP–dependent taurocholate transport was also observed in membrane vesicles from mutant rats deficient in the ATP–dependent transport of cysteinyl leukotrienes and related amphiphilic anions. Substrates of the P–glycoprotein (gp170), such as verapamil and doxorubicin, did not interfere with the ATP–dependent transport of taurocholate.
Reconstitution of purified gp 110 into liposomes resulted in an ATP–dependent uptake of [H]taurocholate. These results demonstrate that gp110 functions as carrier in the ATP–dependent transport of bile salts from the hepatocyte into bile. This export carrier is distinct from hitherto characterized ATP–dependent transport systems.
Significance of Igm Antibody to Hepatitis C Virus in Patients With Chronic Hepatitis C
Authors: Brillanti Stefano , Masci Caterina , Ricci Piero , Miglioli Mario , Barbara Luigi 
Published: March 2007

We assessed the correlation between the positivity for serum IgM antibody to hepatitis C virus and the activity of liver disease in patients with chronic hepatitis C virus infection. Serum samples were taken from 10 antibody to hepatitis C virus–positive asymptomatic patients with normal serum ALT levels, from 14 untreated patients with clinically and histologically proven chronic hepatitis C and from 26 patients with clinically and histologically proven chronic hepatitis C assigned to receive recombinant interferon α–2a (6 million IU three times a week for 6 mo). Each serum specimen was tested for IgM antibody to hepatitis C virus–associated C 100–3 antigen by enzyme–linked immunosorbent assay. Patients were observed for at least 12 mo.
All 10 patients with normal ALT values tested negative for IgM antibody to hepatitis C virus. In contrast, 33 of 40 (82%) patients with chronic hepatitis C had IgM antibody to hepatitis C virus, and a positive correlation was seen between the ALT level and the level of IgM antibody to hepatitis C virus (r = 0.803, p < 0.001).
During interferon treatment, ALT levels declined into the normal range in 18 of 26 treated patients (69%) and remained normal after stopping treatment in 8 patients (31%). In untreated patients, in treated patients who did not respond to interferon treatment and in responder patients who relapsed, no significant changes in IgM antibody to hepatitis C virus levels were seen during the study period. In contrast, IgM antibody to hepatitis C virus became undetectable by the end of interferon treatment in seven of eight patients with a sustained response.
In conclusion, we found a positive correlation between the presence of serum IgM antibody to hepatitis C virus and the activity of the hepatitis C–induced liver disease. In patients with chronic hepatitis C showing a response to α–interferon treatment, the disappearance of IgM antibody to hepatitis C virus predicted that the response would be sustained. (Hepatology 1992;15:998-1001).
Hepatitis C Viremia in Patients With Hepatitis C Virus Infection
Authors: Lok Anna S.F. , Cheung Ramsey , Chan Rachel , Liu Vincent 
Published: March 2007

Sera from 103 patients were tested for hepatitis C virus RNA by nested polymerase chain reaction assay. Using primers from the highly conserved 5′untranslated region, we detected hepatitis C virus RNA in 67 (88.2%) of 76 patients positive for antibody to hepatitis C virus by both second–generation and neutralization enzyme immunoassays. Hepatitis C virus RNA was detected in 93% of patients who had been infected for 10 yr or less and in 89% of those who had been infected for longer than 10 yr. Hepatitis C virus RNA was detected in all patients with chronic hepatitis, active cirrhosis or hepatocellular carcinoma and in 50% of those with nonspecific reactive hepatitis or inactive cirrhosis. Hepatitis C virus RNA was not detected in sera from 22 patients negative for antibody to hepatitis C virus or in 5 patients positive for antibody to hepatitis C virus by second–generation but not by neutralization enzyme immunoassay. Using primers from the less conserved nonstructural region 4, we detected hepatitis C virus RNA at a lower frequency, in 66% of patients who were positive for antibody to hepatitis C virus by both secondgeneration and neutralization enzyme immunoassays. The detection rate was higher in patients with frequent parenteral exposure.
Our study showed that hepatitis C viremia can be detected in most patients with hepatitis C virus infection, including those with long–standing infection or advanced liver disease. (Hepatology 1992;15:1007-1012).
Polymorphism of Alcohol Dehydrogenase, Alcohol and Aldehyde Dehydrogenase Activities: Implication in Alcoholic Cirrhosis in White Patients
Authors: Poupon Renee E. , Nalpas Bertrand , Coutelle Christiane , Fleury Benoit , Couzigou Patrice , Higueret Denise 
Published: March 2007

Two types of factors can theoretically modulate alcohol metabolism toward increased acetaldehyde production. These factors are the following: (a) individual, genetically determined isoenzymes with distinct catalytic properties, and (b) modifications of enzyme activity induced by alcohol itself or liver damage. To investigate the respective roles of these factors in white individuals, we studied the alcohol dehydrogenase phenotype, together with liver alcohol dehydrogenase and aldehyde dehydrogenase activities, in 161 patients. Patients with alcoholic cirrhosis (n = 31) were compared with three types of controls: patients with nonalcoholic cirrhosis (n = 25) and excessive (n = 62) and moderate drinkers (n = 43) without liver disease. No association between alcohol dehydrogenase—3 phenotype and alcoholic cirrhosis was found. The prevalence of atypical alcohol dehydrogenase in the four groups was less than 1%. Patients with cirrhosis, regardless of its cause, had significantly lower alcohol dehydrogenase activity than the patients without cirrhosis (p<0.05 and p<0.01 vs. excessive and moderate drinkers, respectively). Among the noncirrhotic patients, alcohol dehydrogenase activity was significantly lower in the excessive drinkers than in the moderate drinkers (p<0.001). Aldehyde dehydrogenase activity was not different between cirrhosis–free excessive and moderate drinkers; in contrast, compared with these two groups, it was significantly lower in the two cirrhosis groups (p<0.01).
These results suggest that no phenotypic pattern of alcohol dehydrogenase—3 associated with alcoholic cirrhosis in white patients exists, that liver alcohol dehydrogenase activity falls as a consequence of both alcohol abuse and cirrhosis and that liver aldehyde dehydrogenase activity is unaffected by alcohol abuse and only falls after the onset of cirrhosis. (Hepatology 1992;15:1017–1022).
Effect of Simvastatin, Ursodeoxycholic Acid and Simvastatin Plus Ursodeoxycholic Acid on Biliary Lipid Secretion and Cholic Acid Kinetics in Nonfamilial Hypercholesterolemia
Authors: Mazzella Giuseppe , Parini Paolo , Festi Davide , Bazzoli Franco , Aldini Rita , Roda Aldo , Tonelli Domenica , Cipolla Antonio , Salzetta Antonio , Roda Enrico 
Published: March 2007

It has been recently shown that the newest hypocholesterolemic agent, simvastatin, lowers the biliary cholesterol saturation index and that its association with ursodeoxycholic acid renders it more effective. To determine the mechanism by which simvastatin decreases the biliary cholesterol saturation index, we evaluated hepatic secretion rates of cholesterol, bile acids and phospholipids, and cholic acid pool size, turnover and synthesis in eight hyperlipidemic patients (five women and three men, age range = 38 to 65 yr). These assessments were conducted before treatment, after 4 wk of simvastatin (40 mg/day), after 4 wk of ursodeoxycholic acid (600 mg/day) and after a further 4 wk of a combination therapy of simvastatin (40 mg/day) plus ursodeoxycholic acid (600 mg/day).
The cholesterol saturation index was significantly reduced with simvastatin (from 1.51 ± 0.10 to 0.94 ± 0.05, mean ± S.E.; p<0.02), with ursodeoxycholic acid (from 1.51 ± 0.10 to 0.86 ± 0.03, mean ± S.E.; p<0.02) and with the combination of simvastatin plus ursodeoxycholic acid (from 1.51 ± 0.01 to 0.70 ± 0.05, p<0.02). The cholesterol saturation index during combination therapy was significantly lower (p<0.02) than that reached during the use of simvastatin and ursodeoxycholic acid. Both simvastatin and ursodeoxycholic acid significantly reduced the hepatic secretion rate of cholesterol (from 130 ± 14 μmol/hr to 81 ± 12 μmol/hr, p<0.01, and 70 ± 9 μmol/hr, p<0.01) without affecting bile acid and phospholipid outputs. The combination induced a significantly greater decrease of biliary cholesterol output (from 130 ± 14 to 53 ± 5 μmol/hr). Cholic acid pool size, synthesis and turnover rate were not affected by simvastatin administration, but ursodeoxycholic acid and the combination therapy significantly increased (p<0.02) the turnover of cholic acid. Our study shows that simvastatin decreases the cholesterol saturation index by reducing the biliary cholesterol secretion rate and that a synergistic effect is obtained by the addition of ursodeoxycholic acid. (Hepatology 1992;15:1072-1078).
Effect of Galactosamine on Hepatic Carbohydrate Metabolism: Protective Role of Fructose 1,6–Bisphosphate
Authors: de Oliveira Jarbas R. , Rosa Jose Luis , Ambrosio Santiago , Bartrons Ramon 
Published: March 2007

Intraperitoneal administration of galactosamine (400 mg/kg body wt) to rats results in reversible liver cell injury that is related to a dose–dependent depletion of uridine phosphates by formation of UDP–sugar derivatives. This damage was monitored through changes in serum enzymatic activities that increased after the first 6 hr of drug administration. Glycemia and serum albumin remained stable during liver injury, whereas cholesterol and triglycerides decreased. To maintain plasma glucose concentration, the hepatic carbohydrate metabolism was greatly altered. Glycogen dropped during the first hours, remaining low for up to 48 hr. Fructose 2,6–bisphosphate and ATP levels decreased even faster than glycogen, with lactate following a similar diminution and being restored in parallel with both metabolites. The reduction in fructose 2,6–bisphosphate can be explained by changes in the substrates or modulators of the 6–phosphofructo–2–kinase/fructose 2,6–bisphosphatase, because neither the cyclic AMP levels nor the activity ratio of the enzyme were modified.
Simultaneous administration of galactosamine and fructose 1,6–bisphosphate (2 gm/kg) prevented liver cell death, as monitored by serum enzyme activities. Furthermore, the bisphosphorylated metabolite had protective effects on the changes in liver calcium content and ATP and fructose 2,6–bisphosphate concentrations. In contrast, fructose, fructose–1–phosphate and fructose–6–phosphate had no significant protection. Fructose 1,6–bisphosphate might decrease galactosamine toxicity by increasing fructose 2,6–bisphosphate and ATP levels, the changes in both metabolites probably being related. The significance of these findings with respect to the mechanism of galactosamine–induced liver injury is also discussed. (Hepatology 1992;15:1147-1153).
Intracellular Calcium As A Second Messenger for Human Hepatocyte Growth Factor in Hepatocytes
Authors: Kaneko Akira , Hayashi Norio , Tsubouchi Hirohito , Tanaka Yuji , Ito Toshifumi , Sasaki Yutaka , Fusamoto Hideyuki , Daikuhara Yasushi , Kamada Takenobu 
Published: March 2007

Human hepatocyte growth factor is a newly discovered substance that stimulates DNA synthesis in vitro. In this study, we examined intracellular Ca2+ movement as one of the second messengers for human hepatocyte growth factor in primary–cultured hepatocytes. The addition of hHGF induced Ca2+ oscillation, but the frequency of oscillations varied from cell to cell. We also saw marked intercellular heterogeneity in the initial latent period for the Ca2+ response; the mean latent period was rather longer than those seen with phenylephrine and vasopressin. This difference in the initial latent period may be due to the difference in the pathways of Ca2+ elevation.
Duration of culture determined the number of human hepatocyte growth factor—responsive cells; their number peaked at 2 to 5 hours of confluent culture, whereas the peak was earlier in a low–density culture. These changes in responsiveness during culture can be explained by the cell cycle—dependent sensitivity to human hepatocyte growth factor of hepatocytes. The Ca2+ response to human hepatocyte growth factor was dose dependent; 10-10 mol/L hHGF gave the highest Ca2+ response, similar to the dose–response curve of DNA synthesis. We even observed the Ca2+ response in the Ca2+–free buffer, so the increase in Ca2+ was considered due to release from intracellular Ca2+ stores.
These results suggest that human hepatocyte growth factor causes the intracellular Ca2+ elevation in the early stage of the cell cycle and that it plays important roles in the signal transduction systems for human hepatocyte growth factor and the proliferation of hepatocytes. (Hepatology 1992;15:1173-1178).
Isolation and Characterization of the Mannose Receptor From Human Liver Potentially Involved in the Plasma Clearance of Tissue–Type Plasminogen Activator
Authors: Otter Marlies , Žočková PETRA , Kuiper Johan , Van Berkel Theo J.C. , Barrett-Bergshoeff Marrie M. , Rijken Dingeman C. 
Published: March 2007

Various studies have shown that mannose receptors rapidly eliminate glycoproteins and microorganisms bearing high mannose-type carbohydrate chains from the blood circulation. The purpose of this study was to characterize the mannose receptor in the liver, which in vivo is involved in the rapid clearance of tissue–type plasminogen activator from the circulation.
Human liver membranes were solubilized in Triton X–100, and the solution was applied to a tissue–type plasminogen activator Sepharose column. Bound proteins were eluted with ethylenediaminetetraacetate (10 mmol/L). A second, similar purification step rendered a single liver protein of 175,000 daltons. A combination of ligand blotting and a chromogenic assay for tissue–type plasminogen activator demonstrated that the identified liver protein is a mannose receptor because it bound tissue–type plasminogen activator, this tissue–type plasminogen activator binding being fully inhibited by 0.2 mol/L D–mannose. Western–blot analysis revealed that the isolated liver protein is immunologically identical to the human mannose receptor from placenta. Treatment of the liver protein and the placenta mannose receptor with trypsin yielded the same pattern of proteolytic degradation products as identified on sodium dodecyl sulfate-polyacrylamide gel electrophoresis.
We conclude that the physiologically relevant mannose receptor for tissue–type plasminogen activator clearance isolated from human liver is immunologically and structurally similar to or identical with the human mannose receptor isolated from placenta. (Hepatology 1992;16:54-59.)
Cholesterol Metabolism in Human Gallbladder Mucosa: Relationship to Cholesterol Gallstone Disease and Effects of Chenodeoxycholic Acid and Ursodeoxycholic Acid Treatment
Authors: Sahlin Staffan , Ahlberg Jon , Reihnér Eva , Starhlberg Dagny , Einarsson Kurt 
Published: March 2007

The objective of this study was to investigate cholesterol metabolism in human gallbladder mucosa, especially in relation to hepatic cholesterol metabolism, gallstone disease and treatment with bile acids. Gallbladder mucosa and liver tissue samples were collected in 44 patients undergoing cholecystectomy; 30 had cholesterol gallstones and the rest were stone free. Ten of the gallstone patients were treated with chenodeoxycholic acid and eight received ursodeoxycholic acid, with a daily dose of 15 mg/kg body wt, for 3 wk before surgery.
The 3–hydroxy–3–methylglutaryl coenzyme A reductase activity, governing cholesterol synthesis, was considerably lower in the gallbladder mucosa than in liver tissue (28 ± 6 and 120 ± 40 pmol/min/mg protein). The acyl coenzyme A:acyltransferase activity in the gallbladder mucosa catalyzing the esterification of cholesterol was, on the other hand, several times higher than corresponding activity in the liver (92 ± 23 and 11 ± 2 pmol/min/mg protein). In the presence of exogenous cholesterol, the acyl coenzyme A:acyltransferase activity increased about twofold in the gallbladder mucosa.
The acyl coenzyme A:acyltransferase activity of the gallbladder mucosa from untreated gallstone patients was not stimulated further by the addition of exogenous cholesterol. Otherwise, there were no significant differences in acyl coenzyme A:acyltransferase and 3–hydroxy–3–methylglutaryl coenzyme A reductase activities in the gallbladder mucosa of gallstone patients compared with gallstone–free controls.
Treatment with chenodeoxycholic and ursodeoxycholic acids did not affect the 3–hydroxy–3–methylglutaryl coenzyme A reductase activity of the gallbladder mucosa but reduced the acyl coenzyme A:acyltransferase activity by 60% to 65%. A positive correlation was obtained between the cholesterol concentration in bile and the acyl coenzyme A:acyltransferase activity in the gallbladder mucosa in the whole series of patients (Spearman's rank–order correlation coefficient [rS] = 0.42, p < 0.05).
We conclude that human gallbladder mucosa has a lower 3–hydroxy–3–methylglutaryl coenzyme A reductase activity but acyl coenzyme A:acyltransferase activity several times higher than that in liver tissue. Disturbance of cholesterol metabolism in the gallbladder mucosa, which might contribute to the high cholesterol content of gallbladder bile in patients with cholesterol gallstones, was not found. (Hepatology 1992;16:320-326.)
Immunomodulatory Effects of Ursodeoxycholic Acid on Immune Responses
Authors: Yoshikawa Masahide , Tsujii Tadasu , Matsumura Keisuke , Yamao Junnichi , Matsumura Yoshinobu , Kubo Ryouichi , Fukui Hiroshi , Ishizaka Shigeaki 
Published: March 2007

Ursodeoxycholic acid was recently recognized as an effective agent in the treatment of primary biliary cirrhosis. Experimental evidence supporting the usefulness of ursodeoxycholic acid as a potentially beneficial therapeutic agent for primary biliary cirrhosis has been reported from the biochemical and physiological aspects.
In this study, we investigated the direct effects of ursodeoxycholic acid on immunoglobulin and cytokine production in vitro using plaque–forming cell assay and enzyme–linked immunosorbent assay. It was demonstrated that ursodeoxycholic acid suppressed the production of IgM, IgG and IgA induced by Staphylococcus aureus Cowan I in peripheral blood mononuclear cells derived from healthy subjects and patients with primary biliary cirrhosis and also in human B lymphoma cell lines. Furthermore, ursodeoxycholic acid suppressed interleukin–2 and interleukin–4 production induced by concanavalin A and interferon–γ production induced by polyinosinic–polycytidylic acid, but it did not affect interleukin–1 and interleukin–6 production induced by lipopolysaccharide in peripheral blood mononuclear cells. In addition, ursodeoxycholic acid suppressed the concanavalin A–induced thymocyte proliferation mediated by interleukin–1. Cytotoxicity against lymphocytes was not observed at the concentrations of ursodeoxycholic acid used. These results suggest that the beneficial effect of ursodeoxycholic acid in primary biliary cirrhosis is mediated in part by immunosuppression. (Hepatology 1992;16:358-364.)
Increased Tissue–Type Plasminogen Activator Activity in Orthotopic But Not Heterotopic Liver Transplantation: the Role of the Anhepatic Period
Authors: Bakker Minke C. , Metselaar Herold J. , Groenland Theo N. , Gomes Maria J. , Knot Eduard A.R. , Hesselink Eric J. , Schalm Solco W. , Stibbe Jeanne , Terpstra Onno T. 
Published: March 2007

The major cause of the increased tissue–type plasminogen activator activity during orthotopic liver transplantation is still unclear. Both the lack of hepatic clearance of tissue–type plasminogen activator in the anhepatic period and increased endothelial release from the graft on reperfusion have been proposed as the major causes. Heterotopic liver transplantation avoids the resection of the host liver and is a useful model to help differentiate between these two possibilities. In this study the fibrinolytic system was evaluated in 10 orthotopic liver transplantations, 18 heterotopic liver transplantations and a control group of 10 partial hepatic resections.
A marked increment in tissue–type plasminogen activator activity, from 0.2 to 5.2 IU/ml (p <0.02), was observed during the anhepatic period of orthotopic liver transplantation, which rapidly normalized after reperfusion. In contrast, tissue–type plasminogen activator activity levels remained normal in heterotopic liver transplantation and partial hepatic resections. In orthotopic liver transplantation and in heterotopic liver transplantation no increase occurred in tissue–type plasminogen activator activity after reperfusion. The first venous hepatic outflow after reperfusion did not contain elevated tissue–type plasminogen activator activity levels. Plasma degradation products of fibrin and fibrinogen increased during the anhepatic period of orthotopic liver transplantation (from 2.60 to 8.80 μg/ml [p <0.008] and from 0.40 to 1.60 μg/ml [p <0.04], respectively) and remained elevated thereafter. In heterotopic liver transplantation and partial hepatic resections these levels remained low.
In conclusion, the lack of hepatic clearance during the anhepatic period is probably the most important factor in the evolution of increased tissue–type plasminogen activator activity during orthotopic liver transplantation. (Hepatology 1992;16:404-408.)