Screening urinary bile acids for genetic defects in bile acid synthesis?
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Bile Acids and Salts↗
Biomedical subjects
B Tuchweber
Publications and source records attributed to B Tuchweber.
Effect of phalloidin on cholestasis, hemodynamics, and microcirculation in isolated perfused rat liver.
In this study, the possible role of the hepatic microcirculation in phalloidin-induced cholestasis and hepatotoxicity was examined in isolated perfused rat livers (IPRL). Administration of a phalloidin bolus (1 mg/kg body weight) through the portal vein induced an immediate reduction of bile flow. In 16.9 minutes, bile flow was 50% lower than basal values. Portal pressure was only increased in 60 minutes after phalloidin injection and increased sharply from this time up to the end of perfusion (90 minutes). Under these conditions, phalloidin did not induce liver cell cytolysis, as assessed by aspartate transaminase (AST) and lactate dehydrogenase (LDH) release in the perfusate effluent. Under electron microscopy, hepatocytic vacuolization was mild 15 minutes after phalloidin administration but increased with time. At the end of perfusion, the hepatic architecture was markedly altered; erythrocyte accumulation was observed in both sinusoids and hepatocyte vacuoles. Evaluation by multiple indicator dilution curves showed that extravascular volume (EVV) was significantly affected by phalloidin. It was augmented in 30 minutes after phalloidin administration with values increasing gradually over time. Neither vascular nor cellular volume was altered. The hepatic swelling may be attributed to enlargement of the extravascular space of the liver. These results indicate that changes in the liver microcirculation are not the primary cause of phalloidin-induced cholestasis in the IPRL.
Animals↗
Structural and functional alterations of hepatocytes during transient phalloidin-induced cholestasis in the rat.
To study the relationship between the dynamic actin web and bile secretion, we developed an acute model of cholestasis, using phalloidin, and examined sequential morphologic and biochemical events in rat liver. Biliary function (bite flow, bile, and canalicular membrane components) and cellular integrity (release of hepatic enzymes in serum and bile, canalicular structure, and microfilaments distribution) in rats given a single iv dose of phalloidin (0.8 mg/kg body weight) were assessed at 15, 45, and 90 min, 24 hr, and 5 days postinjection. Bile flow decreased significantly at 45 and 90 min, but cholestasis was transient since bile secretion returned to control levels at 24 hr. The biliary bile acid secretion rate was not modified during the same time period, indicating that cholestasis may have been due to impairment of the bile acid independent component of bile flow. Serum alanine aminotransferase and lactate dehydrogenase as well as biliary alkaline phosphatase and alkaline phosphodiesterase-1 activities were not altered by phalloidin treatment. These data, coupled with morphologic studies, provide no evidence of cell damage. Electron microscopy revealed that the pericanalicular actin web in both centrilobular and periportal hepatocytes was increased at 90 min and further enlarged at 24 hr and 5 days after phalloidin injection. At all time periods, the canalicular structure was well preserved. Na+K+ -ATPase and Mg2+ -ATPase activities in membrane fractions enriched in bile canalicular complexes decreased significantly at 15 min and remained low up to Day 5. Mg2+ -ATPase activity returned to control levels by Day 5. The lipid constituents of liver cell membranes enriched in canalicular complexes showed no significant variations 90 min after toxin treatment but, at 24 hr, phospholipid content rose and membrane fluidity increased. These results clearly indicate that the bile flow variation after a single low dose of phalloidin can be dissociated from specific pericanalicular microfilament distribution, lending further support to the view that normal biliary function is not strictly dependent on the integrity of the actin filament network.
Actin Cytoskeleton↗
Cholesterol-lowering effect of soyabean lecithin in normolipidaemic rats by stimulation of biliary lipid secretion.
The purpose of the present study was to assess the role of the liver in the plasma-cholesterol-lowering effect of soyabean lecithin. Normolipidaemic rats were fed on lecithin-enriched or control diets with the same amount of protein. The lecithin diets contained 200 g/kg high-fat commercial semi-purified soyabean lecithin (230 g/kg total lipids as soyabean phosphatidylcholine) or 200 g/kg high-fat purified soyabean lecithin (930 g/kg total lipids as soyabean phosphatidylcholine). The control diets were a lowfat diet (40 g fat/kg) and a high-fat triacylglycerol-rich diet (200 g fat/kg). The high-fat diets were isoenergetic. The cholesterol-lowering effect of the lecithin-enriched diets was associated with significantly lower levels of plasma total- and HDL-cholesterol and significantly higher levels of bile phosphatidylcholine (PC), bile salts and cholesterol. These findings suggest that the liver plays a major role in the reduction of plasma cholesterol, the increased biliary lipid being provided by both HDL and the hepatic microsomal pools of PC and cholesterol.
Animals↗
Lymphatic absorption of retinol in young, mature, and old rats: influence of dietary restriction.
Earlier studies have shown that hepatic vitamin A stores increase with age and that rats subjected to life-long dietary restriction (DR) have greater hepatic retinoid concentrations than ad libitum-fed rats. It was suggested that these changes may be attributed to altered intestinal absorption, and so we measured retinol absorption in 3, 12, and 22 month-old female Sprague-Dawley rats fed ad libitum (AL) or a restricted diet (40%) enriched (DR+) or not (DR) with vitamins and minerals. An in vivo model was used and lymph collected from the mesenteric duct while rats were infused a micellar solution containing [3H]retinol into the proximal duodenum. Aging significantly decreased lymph flow, and at all ages DR and DR+ rats exhibited a higher flow than age-matched AL rats. Absorption of retinol was not significantly modified by age in AL and DR+ rats. However, in the DR group, there was a marked decrease in absorption between 3 and 12 months of age. Retinol absorption was significantly higher in 12 and 22 month-old DR+ rats than in age-matched AL rats, a finding that may be explained by both higher lymph flow rate and higher long-term vitamin A intake per body weight. In conclusion, the increased content of vitamin A in the livers of older AL rats is not associated with changes in intestinal absorption. In DR rats, however, retinoid accumulation in the liver may be explained by increased intestinal absorption of the vitamin, though other mechanisms may be involved. A possible explanation may be a decreased output of retinol from the liver as a result of lower metabolic needs. The lower serum vitamin A concentrations observed in DR rats would tend to support this hypothesis.
Absorption↗
Proliferation and phenotypic modulation of portal fibroblasts in the early stages of cholestatic fibrosis in the rat.
The animal model of hepatic fibrosis induced by bile duct ligation represents an experimental model of human chronic biliary fibrosis. Much attention has been given to the hepatic stellate cell (HSC), or perisinusoidal cell, as the source of the extracellular matrix proteins. However, in the bile duct ligation model, mesenchymal cells other than HSC may be involved in the early stages of fibrosis development. The current study examined, in Sprague-Dawley rats, proliferation in different liver cell subpopulations as well as expression of alpha-smooth muscle (SM) actin and desmin in portal fibroblasts and HSC at 6 hours and 1, 2, 3, and 7 days after bile duct ligation. Kinetics of liver cell proliferation and of phenotypic modulation of portal fibroblasts and HSC (expression of alpha-SM actin and desmin) was evaluated by immunocytochemistry, immunofluorescence, and immunoelectron microscopy using immunogold technique. In sham-operated animals, the evaluation of proliferation in various liver cell subpopulations revealed nonsignificant changes compared with nonoperated rats. alpha-SM actin was detected in vessel walls but was absent in cells of portal tract and parenchyma. Desmin was expressed in vessel walls and in some fibroblastic cells of portal stroma (8.2 cells/unit area) as well as in HSC in acinar Zones 1 and 3 (15.6 cells/unit area and 7.1 cells/unit area, respectively). In bile duct-ligated rats, 24 and 48 hours after ligation, marked proliferations of bile duct epithelial cells (labeling indices 36.8% and 29.5%, respectively) and of periductular fibroblasts (labeling indices 16.7% and 31.0%, respectively) were observed; thereafter, proliferation decreased for both populations (labeling indices at 7 days 12.0% and 11.6%, respectively). HSC proliferation increased gradually until the third day (labeling index 18.6%) and then leveled off. Immunocytochemistry and immunoelectron microscopy revealed a significant number of cells expressing alpha-SM actin 72 hours after bile duct ligation in the stroma adjacent to proliferating ductules. The number of alpha-SM actin-positive cells increased until the seventh day (251.6 cells/unit area). At all times examined, the distribution of alpha-SM actin was restricted to the connective tissue stroma adjacent to proliferating ductules; alpha-SM actin was not expressed in HSC of the lobule. An expansion of desmin expression was noted in fibroblastic cells in stroma surrounding proliferating ductules until 72 hours after bile duct ligation (74.7 cells/unit area) followed by a plateau. At this time, desmin expression increased also in HSC; as in controls, the number of positive cells was greater in Zone 1 (31.8 cells/unit area) than in Zone 3 (18.5 cells/unit area). Double immunofluorescence staining detected by confocal microscopy showed that the majority of portal fibroblastic cells expressing alpha-SM actin was desmin negative 48 hours after bile duct ligation. From 72 hours, portal fibroblastic cells coexpressing alpha-SM actin and desmin appeared, and their proportion increased until 7 days. The present findings indicate that in the early phase of bile duct ligation, there is a marked and transient proliferation of bile duct epithelial cells associated with proliferation of portal periductular fibroblasts, which rapidly express alpha-SM actin. This fibroblastic population may play a dominant role in the early portal fibrosis after bile duct ligation.
Actins↗
Malondialdehyde-modified HDL leads to accumulation of cholesterol in rat liver endothelial cells.
In order to study in vivo the effect of modified high density lipoprotein (HDL) on the movement of free cholesterol to liver cells and bile, we injected i.v. into rats, native or malondialdehyde modified HDL labelled with [14C]cholesterol. Bile analysis indicated that the contribution of labelled cholesterol to bile acid secretion was diminished in the group receiving MDA-modified HDL when compared to control group. On the other hand, the liver analysis revealed higher radioactivity in the treated group. A separation of liver cells into parenchymal, endothelial, and kupffer at 90 min after the injection of MDA-modified HDL or native HDL indicated that the endothelial cell uptake of labelled free cholesterol from MDA-modified HDL was 2.6-fold higher than for native HDL. It is suggested that liver endothelial cells may be involved in the protection against atherogenoic oxidized lipoprotein. However, with regard to our finding, the uptake of cholesterol from modified HDL was detrimental to bile acid secretion.
Animals↗
Effect of agents which modify reticuloendothelial system function on acute phalloidin-induced lethality and hepatotoxicity in mice.
The relationship between reticuloendothelial system (RES) function and acute phalloidin intoxication was studied in mice. Pretreatment with compounds that stimulate (zymosan) or depress (methyl palmitate and praseodymium nitrate, Pr(NO3)3) the RES resulted in protection against phalloidin-induced lethality and hepatotoxicity, as assessed by morphological analysis. However, triolein (which stimulates the RES) was ineffective against phalloidin. The timing of pretreatment with the effective compounds showed a correlation between modified in vivo RES function (phagocytosis) and protection against the toxin. The effects of pretreatment with zymosan and Pr(NO3)3 were further characterized. Hepatic damage induced by phalloidin was significantly decreased by these agents, as judged by morphological analysis as well as by serum aspartate aminotransferase and alanine aminotransferase release. This study also showed that there was no correlation between the capacity of Kupffer cells to produce nitrite and prophylaxis against phalloidin. However, liver cell proliferation was increased by zymosan and Pr(NO3)3 in parallel with protection against the toxin. Furthermore, freshly isolated hepatocytes from zymosan- or Pr(NO3)3-treated mice were less sensitive to phalloidin in vitro. These results indicate that the protective effect of these agents against phalloidin-induced hepatotoxicity may be mediated by their mitogenic properties.
Animals↗
Bile formation and hepatic plasma membrane composition in guinea-pigs and rats.
We compared bile formation, and biliary and liver plasma membrane composition in guinea-pigs and rats in an attempt to explain the observation that the bile flow rate and the bile acid independent fraction of bile flow (BAIF) in guinea-pigs is about five to seven times higher than in rats. Analysis of electrolytes in bile showed that bicarbonate was significantly [acid] higher in guinea-pigs while Cl-, phosphate and Ca2+ were markedly lower than in rats. High bile independent secretion in guinea-pigs was associated with a significantly lower concentration of total bile acid, phospholipid and cholesterol than in rats. Bile acid distribution studies showed that glycine conjugated chenodeoxycholate and ketolithocholate were the main bile acids in guinea-pigs, while taurine conjugated cholate and muricholate were the predominant bile acids in rats. Total fatty acid analysis of bile indicated that in rats the major fatty acids were palmitic acid (C16:0) and linoleic acid (C18:2, n-6). In guinea-pigs, the contribution of these fatty acids was lower than in rats and compensated with a significantly higher percentage of oleic acid (C18:1, n-9). Concentrations of anionic polypeptide fraction (APF), an acidic calcium binding apoprotein closely associated with biliary phospholipid and cholesterol secretion was also significantly lower in guinea-pigs. Canalicular plasma membrane analysis showed that as compared with rats, specific activities of Na+,K+ ATPase, and cholesterol and phospholipid content were markedly lower in guinea-pigs.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine Triphosphatases↗
Role of the myofibroblast differentiation during liver fibrosis.
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Actins↗
Malondialdehyde-modified high-density lipoprotein cholesterol: plasma removal, tissue distribution and biliary sterol secretion in rats.
Evidence has been accumulating for the putative role of chemically or oxidatively altered lipoproteins in accelerating events in the atherogenic process. In this study, the movement of free cholesterol from native high density lipoprotein (HDL) and malondialdehyde (MDA)-modified HDL to the liver for biliary cholesterol secretion and bile acid transformation was examined in vivo. To this end, HDL from normal donor rats was isolated, conjugated with MDA, labelled with [14C]cholesterol and injected i.v. into rats with bile diversion. While the 6 h collection revealed no substantial differences in bile flow, less 14C excretion was recovered in the fresh bile of animals receiving MDA-modified HDL. Bile analysis indicated that a significant decline in labelled bile acid secretion characterized these rats. Compared with controls, MDA-modified HDL also caused an enhanced accumulation of [14C]cholesterol in the liver and the kidneys, with reduced delivery to the sites of steroidogenesis, i.e., the adrenals and testes. No plasma removal differences were noted in the HDL of both groups of rats. Thus, modification of HDL by MDA seems to impair the tissue distribution of its cholesterol moiety, particularly in the liver, where it accumulates at the expense of bile acid transformation.
Animals↗
Short-term feeding of a diet enriched in phospholipids increases bile formation and the bile acid transport maximum in rats.
Earlier studies suggested that the secretory rate maximum (SRm) of bile acid and the cholestasis which occurs after the SRm is reached may be determined by the hepatic or extrahepatic biliary phospholipid pool. We therefore investigated whether bile formation and the bile acid SRm could be influenced by feeding a diet enriched in phospholipids. Male rats were fed phospholipid (PLD) or triacylglycerol (TgD)-enriched diet for 3 days, and bile formation as well as biliary lipid output were measured on the 4th day. In other similarly fed groups, cholic acid was infused in stepwise increasing doses to determine the effect of PLD on the SRm of cholic acid. The plasma lipid levels were significantly lower in PLD and TgD diets compared to basal diet. But, while the levels of total cholesterol (CH), HDL-CH, and phospholipid (PH) were not significantly altered by PLD compared to TgD, the triacylglycerol levels were markedly increased by PLD. In the liver of PLD fed rats, triacylglycerol and CH ester contents decreased by 39 and 62%, respectively, while free CH and PH contents were not significantly changed. The PLD significantly augmented spontaneous bile flow, bile acid, PH and CH secretion rates compared to TgD diet (65, 124, 164 and 654%, respectively). The enhanced biliary secretory function was associated with an increase in pericanalicular vacuoles and diverticuli in centrilobular hepatocytes. Compared to TgD fed rats, PLD rats showed a 2-fold decrease in the ratio of cholic acid/chenodeoxycholic acid in bile and a significant decrease in the % contribution of taurine conjugated BA. The PH fatty acids in bile were similar in both groups except that in PLD group the % contribution of C18:2 was higher than in TgD group. No differences were found in plasma membrane CH/PH content or total fatty acid composition. During bile acid infusion, the SRm and the total cholic acid secreted were significantly higher in the PLD than in the TgD rats. Moreover, the cholestatic response observed after high bile acid dose was markedly reduced by PLD. The results show that short-term feeding of PLD induces changes in CH and bile acid metabolism which result in enhanced biliary output of CH and PH. The enhanced pool of biliary lipid may protect plasma membranes from the deleterious effects of high bile acid concentrations.
Animals↗
Phase I and phase II metabolism of lithocholic acid in hepatic acinar zone 3 necrosis. Evaluation in rats by combined radiochromatography and gas-liquid chromatography-mass spectrometry.
In the present study, lithocholic acid (LCA) metabolism was assessed by radiochromatography and gas-liquid chromatography-mass spectrometry, and its relationship to cholestasis was investigated. In addition, the role of the perivenous zone in LCA-induced cholestasis and LCA biotransformation was examined by using bromobenzene (BZ), a chemical that causes selective necrosis of hepatocytes in this zone. LCA injection induced cholestasis of comparable amplitude in both control and BZ-treated rats. The biliary recovery of bile salts (BS) was 65-70% 2 hr after LCA injection. Excretion of LCA and its cholestatic metabolite, LCA glucuronide, was similar in both groups, although LCA excretion was delayed in BZ-treated animals. The appearance of LCA and LCA glucuronide in bile occurred early, and their proportion decreased with time. Concentrations of choleretic hydroxylated metabolites were low immediately after LCA injection but increased with time. 3 alpha,6 beta-Dihydroxy-5 beta-cholanoic and 3 alpha,6 beta,7 beta-trihydroxy-5 beta-cholanoic acids were the major species arising from LCA, indicating the importance of 6 beta hydroxylation in LCA detoxification in rats. Other metabolites were found, but their contribution was either minor or negligible. Overall amounts of hydroxylated metabolites were comparable in both groups, but trihydroxylated metabolites predominated over their dihydroxylated counterparts in control rats, whereas the production of dihydroxylated forms was more pronounced in BZ-treated animals. These results suggest that the destruction of perivenous hepatocytes does not exacerbate LCA-induced cholestasis, and that there may be an acinar zonation of LCA biotransformation to trihydroxylated metabolites in the rat liver.
Animals↗
Decreased biliary glutathione content is responsible for the decline in bile salt-independent flow induced by ethinyl estradiol in rats.
Glutathione appears to be a major osmotic factor in the generation of bile salt-independent flow (BSIF). This study was designed to investigate its importance in the pathology of 17-alpha-ethinyl estradiol (EE)-induced cholestasis. Five-day EE treatment at the dose level of 5 mg/kg/day significantly decreased bile flow (57% of controls) and biliary glutathione secretion. Evaluation of the contribution of bile salt dependent flow (BSDF), glutathione dependent flow (GSDF) and the bile flow generated independently of both bile salts and glutathione (BS-GSIF) revealed that EE decreased all portions of the flow (63, 44 and 52% of control values, respectively). At 4 and 20 h after a single administration of the same EE dose, a significant diminution of bile flow was noted (decreases of 17 and 29%, respectively) in association with a significant fall in biliary glutathione content. Under these conditions, BSDF and BS-GSIF were not modified (98 and 112% of control BSDF values, respectively; 96 and 99% of control BS-GSIF values, respectively) while GSDF was decreased markedly, representing 65 and 50% of control values. Biliary glutathione secretion was diminished without modification of liver and blood glutathione concentration or redox status following single EE dose whereas, after 5 days of EE treatment, a significant increase in liver glutathione was observed, suggesting that EE may interfere with the glutathione secretory process. This study demonstrates that EE rapidly alters biliary glutathione content, leading to a marked decline in GSDF. This reduction may explain the decrease in BSIF produced by EE at the outset of cholestasis.
Analysis of Variance↗
Protection by indomethacin against the lethality and hepatotoxicity of phalloidin in mice.
The present study examined the possible involvement of endogenous cyclooxygenase-derived factors in the lethality and hepatic hemorrhagic necrosis induced by phalloidin. Mice were pretreated with indomethacin, aspirin or ibuprofen (all inhibitors of cyclooxygenase) and injected with phalloidin (2 mg/kg). The toxin induced 75% lethality and caused severe hemorrhagic necrosis of the liver associated with increased serum levels of AST and ALT. Indomethacin completely prevented the mortality and hepatic damage elicited by phalloidin as judged by morphologic analysis and serum AST and ALT release. The in vitro addition of indomethacin to suspensions of freshly-isolated hepatocytes decreased plasma membrane bleb formation induced by phalloidin. In contrast to indomethacin, aspirin and ibuprofen did not influence phalloidin toxicity in vivo. These results suggest that inhibition of prostanoids per se may not be the sole mechanism of protection by indomethacin.
Alanine Transaminase↗
Moderate long-term physical activity improves the age-related decline in bile formation and bile salt secretion in rats.
This study examined the effect of moderate long-term exercise, begun soon after weaning, on the age-related decline in bile formation and the secretory rate maximum (SRm) of taurocholate (TC), the major bile salt (BS) in rats. Eight-month-old sedentary (S) female Sprague-Dawley rats showed a significant decrease in basal and TC-stimulated bile formation when compared with 2.5-month-old S controls. As in younger rats, decreased biliary phospholipid (PL) output was associated with the TC SRm, but this change appeared much more rapidly in S animals, which also exhibited significant increased plasma lipids and higher TC concentrations in plasma and liver at the end of the TC infusion. Exercise significantly improved bile flow (BF), including the bile salt-dependent and -independent fractions under basal and TC-stimulated conditions in 8 month-old rats. Although all the biliary parameters evaluated were improved, maximal BF and PL secretion values were affected the most and were virtually not different from those obtained in younger S animals. Exercise also significantly lowered the age-related elevation of plasma PL. Thus, moderate long-term exercise exerts a beneficial effect on hepatobiliary function and the BS SRm, an effect that may be attributed in part to increased availability of a biliary PL pool previously implicated in regulation of the BS SRm.
Age Factors↗
Dietary restriction reduces the incidence of NMU-induced mammary tumors and alters retinoid tissue concentrations in rats.
Previous studies suggested a relationship between dietary restriction (DR) effects on mammary carcinogenesis and DR effects on liver retinoids. Therefore, in this study, retinoid concentrations were measured by high-performance liquid chromatography in the plasma, liver, and peripheral organs of DR rats with chemically induced carcinogenesis. Rats were injected with N-methyl-N-nitrosourea (MNU) and maintained on graded levels of DR (reduction of 10-40% from energy ingested by control animals with free access to food). Mammary tumor incidence and multiplicity induced by MNU were reduced in relation to the degree of DR, with virtual prevention occurring at 30% and 40% DR. Total hepatic retinoid concentrations (retinol + retinyl esters) were significantly greater in rats given MNU and subjected to DR, but liver total retinoid content was comparable between the groups. However, plasma retinol concentrations were significantly lower in DR rats than in controls given the carcinogen without DR. Retinoid concentrations were also elevated in adipose tissue, lungs, and intestine of DR rats, while renal concentrations remained unaltered. Retinoid concentrations in mammary glands and mammary tumors were similar in all groups. Thus, in DR rats, vitamin A concentrations in liver and other target tissues are maintained or increased despite decreases in plasma. It remains to be investigated whether these alterations in retinoid content have any relationship to the cancer-preventive effect of DR.
Adipose Tissue↗
Influence of oral treatment with ursodeoxycholic and tauroursodeoxycholic acids on estrogen-induced cholestasis in rats: effects on bile formation and liver plasma membranes.
In this study, we examined whether ursodeoxycholic acid (UDC) and its taurine conjugate, tauroursodeoxycholic acid (TUDC), given per os, can prevent the cholestasis induced in rats by 17-alpha-ethynyl estradiol (EE) and whether this protection is mediated by choleretic activity or altered plasma membrane composition. EE (5 mg/kg body weight/day for 5 days) markedly reduced bile flow and bile salt secretion without significantly affecting plasma membrane composition and function. Treatment with UDC or TUDC (100, 150 or 200 (TUDC only) mumol/100 g body weight/day for 5 days) did not significantly modify bile flow, but the bile salt secretion rate increased in a dose-dependent manner. UDC was the main biliary bile acid secreted in groups given higher doses of UDC or TUDC. At these dose levels, bile acid treatment did not affect plasma membrane fluidity as assessed by fluorescence anisotropy, the cholesterol/phospholipid molar ratio as well as Na+K(+)- and Mg(++)-ATPase activities. The highest dose of UDC and TUDC prevented the reduction of both bile flow and bile salt secretion induced by EE, re-establishing these parameters to the values of the corresponding control for the UDC group. In conclusion, UDC and TUDC, given per os, improve EE-induced cholestasis, an effect that cannot be attributed to choleretic activity or altered plasma membrane composition.
Administration, Oral↗