Biliary lipid secretion and its control. Effect of taurodehydrocholate.
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ABSTRACT:
SUBMITTER: Rahman K
PROVIDER: S-EPMC1148154 | biostudies-other | 1987 Jul
REPOSITORIES: biostudies-other
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Project description:A major determinant of biliary lipid secretion is bile-salt secretion. Taurocholate (TC), a micelle-forming bile salt, was infused continuously at different rates in both isolated perfused livers and biliary-fistula rats. In both of these systems, infusion of TC brought about an elevated secretion of phosphatidylcholine for the duration of the TC infusion period. Initial phospholipid/bile-salt ratios in the bile were higher in the whole-animal model than in isolated livers, but at the higher infusion rates both secreted approx. 6 mol of phospholipid for every 100 mol of bile salt. The secretion of phospholipid, which was maintained even at high rates of bile-salt infusion, suggest a continuous and regulated phospholipid supply and secretion mechanism. In contrast, however, multiple short pulses of TC to the perfused liver, which brought about relatively equal biliary bile-salt output pulses, did not bring about equal phospholipid outputs, since the phospholipid peak size declined with each bile-salt pulse. These experiments taken together suggest either that a threshold (intracellular) bile-salt concentration may be required to 'switch-on' the phospholipid supply and that it may need to be maintained for continuous biliary phospholipid supply to the canalicular membrane.
| S-EPMC1146581 | biostudies-other
Project description:This study was performed to determine the effects of various organic anions on biliary lipid secretion in rats. We infused bile-salt-pool-depleted rats with sodium taurocholate at a constant rate, with or without various organic anions: Indocyanine Green (ICG), bromosulphophthalein (BSP), BSP-glutathione and Phenol Red (PR). BSP decreased biliary secretion of cholesterol and phospholipids in a dose-dependent manner without affecting bile salt secretion (uncoupling), and this change was fully reversible. In contrast, ICG, BSP-glutathione and PR did not cause such an uncoupling of biliary lipids. In addition, the distribution pattern of each organic anion to various lipid particles was determined by gel-permeation chromatography. BSP was predominantly associated with bile salt micelles, whereas vesicular association was dominant for ICG, and both BSP-glutathione and PR formed only self-aggregations. From these data, we concluded that the uncoupling of biliary lipids from bile salt secretion by BSP resulted from the interaction between BSP and bile salt micelles in the bile canaliculus, and that this interaction inhibited the capacity of bile salts to induce the secretion of phospholipids and cholesterol.
| S-EPMC1133038 | biostudies-other
Project description:Exposure of isolated perfused rat livers to either 100 microM-forskolin, a potent activator of adenylate cyclase, or to 0.5 mM-concentrations of the cAMP analogues chlorophenylthio cAMP (CPTcAMP), dibutyryl cAMP (dbcAMP) and 8-bromo cAMP (8BrcAMP), to provoke increases in intracellular concentrations of cAMP, resulted in marked changes in bile volume and composition. Bile flow reached a peak after 10 min, before declining towards control levels, and an increase in several secretory parameters was also observed at this time. At 20 min, a substantial decrease in the output of both phospholipid and cholesterol was evident, and this suppression of secretion was maintained throughout the remainder of the experiment. The order of effectiveness of the cAMP-elevating agents at decreasing biliary lipid output was CPTcAMP greater than forskolin greater than dbcAMP greater than 8BrcAMP. Biliary output of bile acids was essentially unaltered compared with controls; similarly, no decrease in the secretion of protein and triacylglycerols into the perfusion medium was observed. This suggests that the elevation of intracellular levels of cAMP may cause a selective inhibition of biliary lipid output rather than a more general inhibition of hepatic secretion.
| S-EPMC1133713 | biostudies-other
Project description:This study was performed to explore the mechanisms by which sulphobromophthalein (BSP) reduces the secretion of biliary lipid using Sprague-Dawley rats (SDR) and mutant rats with congenital conjugated hyperbilirubinaemia bred from SDR (EHBR). We infused the bile-salt-pool-depleted rats with sodium taurocholate at a constant rate of 160 nmol/min per 100 g body wt. with BSP (12.5, 25 and 50 nmol/min per 100 g body wt.) or BSP-GSH (12.5, 25 and 50 nmol/min per 100 g body wt.). The biliary secretion of BSP and BSP-GSH was markedly impaired in EHBR as compared with that in SDR. BSP reduced the biliary secretion of cholesterol and phospholipids in a dose-dependent manner without affecting the secretion of bile salts and composition of fatty acids in phospholipids in SDR, but had no effect on lipid secretion in EHBR. In contrast, BSP-GSH had no such effect on biliary lipids, either in the SDR or EHBR. In addition, the amount of BSP in the liver of EHBR was in the same range as that of SDR. Therefore it is unlikely that an intracellular mechanism is involved in the phenomenon of uncoupling by BSP. We conclude that the uncoupling of biliary lipids from bile-salt secretion by BSP occurs at the level of the bile canaliculus following the secretion of unconjugated BSP.
| S-EPMC1132498 | biostudies-other
Project description:Recent studies support a role for cholesterol in the development of obesity and nonalcoholic fatty liver disease. Mice lacking the ABCG5 ABCG8 (G5G8) sterol transporter have reduced biliary cholesterol secretion and are more susceptible to steatosis, hepatic insulin resistance, and loss of glycemic control when challenged with a high-fat diet. We hypothesized that accelerating G5G8-mediated biliary cholesterol secretion would correct these phenotypes in obese mice.Obese (db/db) male and their lean littermates were administered a cocktail of control adenovirus or adenoviral vectors encoding ABCG5 and ABCG8 (AdG5G8). Three days after viral administration, measures of lipid and glucose homeostasis were determined, and tissues were collected for biochemical analyses. AdG5G8 increased biliary cholesterol and fecal sterol elimination. Fasting glucose and triglycerides declined, and glucose tolerance improved in obese mice expressing G5G8 compared with mice receiving control adenovirus. These changes were associated with a reduction in phosphorylated eukaryotic initiation factor 2? and c-Jun N-terminal kinase in liver, suggesting alleviation of endoplasmic reticulum stress. Phosphorylated insulin receptor and protein kinase B were increased, indicating restored hepatic insulin signaling. However, there was no reduction in hepatic triglycerides after the 3-day treatment period.Accelerating biliary cholesterol secretion restores glycemic control and reduces plasma triglycerides in obese db/db mice.
| S-EPMC4096285 | biostudies-literature
Project description:Sebaceous glands are skin appendages that secrete sebum onto hair follicles to lubricate the hair and maintain skin homeostasis. In this study, we demonstrated that Cidea is expressed at high levels in lipid-laden mature sebocytes and that Cidea deficiency led to dry hair and hair loss in aged mice. In addition, Cidea-deficient mice had markedly reduced levels of skin surface lipids, including triacylglycerides (TAGs) and wax diesters (WDEs), and these mice were defective in water repulsion and thermoregulation. Furthermore, we observed that Cidea-deficient sebocytes accumulated a large number of smaller-sized lipid droplets (LDs), whereas overexpression of Cidea in human SZ95 sebocytes resulted in increased lipid storage and the accumulation of large LDs. Importantly, Cidea was highly expressed in human sebaceous glands, and its expression levels were positively correlated with human sebum secretion. Our data revealed that Cidea is a crucial regulator of sebaceous gland lipid storage and sebum lipid secretion in mammals and humans.
| S-EPMC4019032 | biostudies-literature
Project description:Hepatitis A virus (HAV) is an unusual picornavirus that is released from cells cloaked in host-derived membranes. These quasi-enveloped virions (eHAV) are the only particle type circulating in blood during infection, whereas only nonenveloped virions are shed in feces. The reason for this is uncertain. Hepatocytes, the only cell type known to support HAV replication in vivo, are highly polarized epithelial cells with basolateral membranes facing onto hepatic (blood) sinusoids and apical membranes abutting biliary canaliculi from which bile is secreted to the gut. To assess whether eHAV and nonenveloped virus egress from cells via vectorially distinct pathways, we studied infected polarized cultures of Caco-2 and HepG2-N6 cells. Most (>99%) progeny virions were released apically from Caco-2 cells, whereas basolateral (64%) versus apical (36%) release was more balanced with HepG2-N6 cells. Both apically and basolaterally released virions were predominantly enveloped, with no suggestion of differential vectorial release of eHAV versus naked virions. Basolateral to apical transcytosis of either particle type was minimal (<0.02%/h) in HepG2-N6 cells, arguing against this as a mechanism for differences in membrane envelopment of serum versus fecal virus. High concentrations of human bile acids converted eHAV to nonenveloped virions, whereas virus present in bile from HAV-infected Ifnar1-/- Ifngr1-/- and Mavs-/- mice banded over a range of densities extending from that of eHAV to that of nonenveloped virions. We conclude that nonenveloped virions shed in feces are derived from eHAV released across the canalicular membrane and stripped of membranes by the detergent action of bile acids within the proximal biliary canaliculus.ImportanceHAV is a hepatotropic, fecally/orally transmitted picornavirus that can cause severe hepatitis in humans. Recent work reveals that it has an unusual life cycle. Virus is found in cell culture supernatant fluids in two mature, infectious forms: one wrapped in membranes (quasi-enveloped) and another that is nonenveloped. Membrane-wrapped virions circulate in blood during acute infection and are resistant to neutralizing antibodies, likely facilitating HAV dissemination within the liver. On the other hand, virus shed in feces is nonenveloped and highly stable, facilitating epidemic spread and transmission to naive hosts. Factors controlling the biogenesis of these two distinct forms of the virus in infected humans are not understood. Here we characterize vectorial release of quasi-enveloped virions from polarized epithelial cell cultures and provide evidence that bile acids strip membranes from eHAV following its secretion into the biliary tract. These results enhance our understanding of the life cycle of this unusual picornavirus.
| S-EPMC5142623 | biostudies-literature
Project description:At high bile-salt-secretion rates the biliary secretion of phospholipids and cholesterol is dependent on that of the bile salts. However, at low bile-salt outputs some secretion remains. Isolated perfused rat livers were used in these experiments in order to study the bile-salt-independent secretion of biliary lipids. The livers were isolated and saline (0.9% NaCl), or phalloidin dissolved in saline, was added to the perfusion fluid after 1 h of liver isolation. The concentration and output of cholesterol was significantly decreased in phalloidin-treated livers compared with the controls, whereas there was no significant decrease in phospholipids; the secretion of cholesterol and phospholipids can thus be uncoupled from each other by the action of phalloidin. These experiments suggest that a proportion of cholesterol gets into bile independently of bile salts and phospholipids. These findings are discussed in relation to the supersaturation of some biles with cholesterol and its relationship to the bile-salt-independent fraction of cholesterol.
| S-EPMC1146983 | biostudies-other
Project description:BackgroundThe protective effect of HDL is mostly attributed to their metabolic function in reverse cholesterol transport (RCT), a process whereby excess cellular cholesterol is taken up from peripheral cells, processed in HDL particles, and later delivered to the liver for further metabolism and biliary secretion. Mechanistically, the purinergic P2Y13 ADP-receptor is involved in hepatic HDL endocytosis (i.e., uptake of both HDL protein + lipid moieties), which is considered an important step of RCT. Accordingly, chow-fed P2Y13 knockout (P2Y13-/-) mice exhibit lower hepatic HDL uptake, which translates into a decrease of hepatic free cholesterol content and biliary cholesterol and phospholipid secretion.FindingsThe aim of this study was to determine the effect of high cholesterol diet (HCD) in P2Y13-/- mice, in order to mimic high dietary cholesterol intake, which is a major cause of dyslipidemia in humans. As previously reported with chow-diet, HCD did not affect plasma lipid levels in P2Y13-/- compared with control mice but decreased hepatic free and esterified cholesterol content (p < 0.05, P2Y13-/- versus control). Interestingly, biliary lipid secretion and macrophages-to-feces RCT were more dramatically impaired in P2Y13-/- mice fed a HCD than chow-diet. HCD did not enhance atherosclerosis in P2Y13-/- compared with control mice.ConclusionThis study demonstrates that high dietary cholesterol intake accentuated the metabolic phenotype of P2Y13-/- mice, with impaired hepatobiliary RCT. Although other animal models might be required to further evaluate the role of P2Y13 receptor in atherosclerosis, P2Y13 appears a promising target for therapeutic intervention aiming to stimulate RCT, particularly in individuals with lipid-rich diet.
| S-EPMC4029266 | biostudies-literature
Project description:BACKGROUND: The liver is a key organ in the metabolism of cholesterol in humans. It is the only organ by which substantial amounts of cholesterol are excreted from the body, either directly as free cholesterol into the bile or after conversion to bile acids. The major part of cholesterol synthesis in the body occurs in the liver. Cholesterol is also taken up by the liver from plasma lipoproteins. The relative contributions of newly synthesised cholesterol and plasma lipoprotein cholesterol to bile acid synthesis and biliary cholesterol secretion, respectively, are not known in detail. AIMS: To determine how a rapid lowering of plasma low density lipoprotein (LDL) and very low density lipoprotein (VLDL) cholesterol influences the biliary secretion rates of cholesterol and bile acids in patients with cholesterol gallstones and complete biliary drainage. In this model with a completely interrupted enterohepatic circulation, the secretion of bile acids equals the new synthesis of bile acids in the liver. PATIENTS: Eight patients with common bile duct stones of cholesterol type undergoing conventional cholecystectomy and choledocholithotomy. METHODS: At operation a balloon occludable Foley catheter attached to a T tube was inserted into the bile duct with the balloon placed just past the distal limb of the T tube. The T tube was allowed to drain the bile externally. One week after the operation the Foley catheter balloon was inflated, creating complete biliary drainage. Twelve hours following the inflation plasma LDL apheresis was carried out for two hours. Bile was collected for 15 minute periods starting one hour before the apheresis and ending two hours after its termination. During the collection of bile, plasma lipids were analysed on several occasions. RESULTS: The plasma level of LDL cholesterol decreased by 26% from (mean (SEM)) 2.19 (0.29) to 1.63 (0.17) mmol/l during the LDL apheresis while high density lipoprotein (HDL) cholesterol in plasma was unaffected. During LDL apheresis apolipoprotein B containing lipoproteins bind to the column, causing a significant decrease of not only plasma LDL but also of VLDL cholesterol. The secretion rate of bile acids decreased significantly by 31% from 131 (38) to 90 (16) mumol/15 minutes (p = 0.045). The output of phospholipids also decreased by 19%. The biliary secretion rate of cholesterol was not, however, affected by the plasma LDL apheresis. CONCLUSIONS: The results suggest that, in patients with cholesterol gallstones and complete biliary drainage, lowering of plasma LDL and VLDL cholesterol reduces the biliary secretion rate--synthesis--of bile acids without affecting the biliary secretion rate of cholesterol.
| S-EPMC1891585 | biostudies-other