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Query: UMLS:C0008370 (cholestasis)
 9,378 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the effect of extrahepatic cholestasis on integrity of the inner mitochondrial membrane, a study was conducted on two groups of rats: sham-operated control animals (N = 10) and rats subjected to extrahepatic cholestasis (EHC, N = 10) by double ligation of the hepatic duct. The animals were observed for 7 days and then sacrificed. The EHC group presented significantly higher serum levels of alanine aminotransferase, total bilirubins and alkaline phosphatase than the controls (P less than 0.01). Basal mitochondrial respiration (state IV), analyzed separately using either alpha-ketoglutarate or alpha-ketoglutarate + pyruvate as substrates, was similar in the two groups (P greater than 0.01). ADP-activated respiration, state III, diminished significantly in the EHC group. The results show that the decrease in mitochondrial function that has been reported by several investigators to occur in EHC is due to mitochondrial alterations not related to the ability of these organelles to maintain the proton gradient, since the inner mitochondrial membrane continued to be energized throughout the observation period.
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PMID:Integrity of liver inner mitochondrial membrane in rats with extrahepatic cholestasis. 182 30

Serum 5'-nucleotidase in rat and man is derived from the plasma membrane rather than the cytosol by the criteria of inhibition with [alpha beta-methylene]ADP and antisera. In individuals with cholestasis the serum enzyme is mainly present as a high-Mr form that in the presence of the zwitterionic detergent Sulphobetaine 14 has the electrophoretic characteristics of liver plasma-membrane ectoenzyme. A minor form of 5'-nucleotidase in cholestatic serum and all the enzyme in normal serum appears to be half the molecular size of the liver plasma-membrane ectoenzyme. 5'-Nucleotidase from both normal and cholestatic rat serum was found to contain a polypeptide chain of apparent Mr 70 000 by immunoblotting techniques. It is suggested that the major form of 5'-nucleotidase in cholestatic serum is an ectoenzyme dimer derived from liver plasma membrane. All of the enzyme in normal serum and some of the enzyme in cholestatic serum is present as an active monomer derived from the ectoenzyme dimer.
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PMID:Characterization of different molecular forms of 5'-nucleotidase in normal serum and in serum from cholestatic patients and bile-duct-ligated rats. 609 64

The effects of postoperative infusion of a hypertonic glucose solution on the blood glucose level, blood ketone body ratio (acetoacetate/beta-hydroxybutyrate), and plasma alanine and proline levels were studied in 70% hepatectomized rabbits (group A) and in rabbits 70% hepatectomized and, in addition, subjected to bile duct obstruction at 12 h after hepatectomy (group B). Glucose infusion was started at the end of hepatectomy and continued for 20 h. The blood glucose level in group A remained at approximately 300 mg/dl throughout the study; however, it reached 789 mg/dl in group B at 20 h. The blood ketone body ratio, which reflects hepatic mitochondrial redox potential, decreased from 0.90 +/- 0.09 in untreated rabbits to 0.38 +/- 0.05 in group A, and to 0.19 +/- 0.03 in group B at 20 h. As the blood ketone body ratio decreased, plasma proline and alanine levels increased rapidly (proline, r = -0.601, p less than 0.02; alanine, r = -0.640, p less than 0.001). In addition, the blood ketone body ratio was positively correlated with the hepatic energy charge level [(ATP + 0.5 ADP)/(ATP + ADP + AMP)] (r = 0.57, p less than 0.001). It is suggested that the entry of glucose and amino acids into the Krebs cycle is inhibited as the blood ketone body ratio decreases, and under such conditions the infused glucose tends to accumulate, resulting in severe hyperglycemia.
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PMID:Changes in blood glucose levels in relation to blood ketone body ratio following hypertonic glucose infusion in 70% hepatectomized rabbits. 646 65

Kinetic patterns of oxydative phosphorylation were studied in rat liver mitochondria in dynamics of cholestasis and after addition of bile acids to mitochondria in vitro. Within the 1 and 3 days of cholestasis mitochondrial synthesis of ATP was decreased due to inhibition of ATP and ADP transport by the bile acids. At the period within 3 and 15 days uncoupling of the oxidative phosphorylation occurred; the phenomenon observed might be a result of impairment in the structure of inner mitochondrial membrane.
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PMID:[Changes in oxidative phosphorylation in rat liver mitochondria during the development of cholestasis]. 745 89

Liver proliferation appears to be dually regulated, in part by cyclic AMP levels. Here we studied the alterations in the stimulatory action of cholera toxin and other agents on the adenylyl cyclase system, as well as the status of Gs and Gi protein subunits during the liver proliferation that follows bile duct ligation in rats. The stimulatory effects of glucagon and vasoactive intestinal peptide (which act through membrane receptors) or guanosine 5'-[beta gamma-imido]triphosphate (which interacts with G proteins) and forskolin (which directly activates the adenylyl cyclase catalytic subunit) on liver adenylyl cyclase activity were blunted in cholestasis. The results indicated an impairment in the stimulatory interaction between the alpha s subunit of Gs protein and the adenylyl cyclase catalytic subunit. Indeed, we observed an important decrease in the stimulation of adenylyl cyclase activity by cholera toxin in cholestasis that was accompanied by a reduced extent of [32P]ADP ribosylation of alpha s protein catalyzed by cholera toxin, as revealed by the poor labeling of the 42,000 Da band in liver membranes from cholestatic rats. However, there was no change in the amount of alpha s or beta proteins as measured with immunoblotting techniques. Experiments on [32P]ADP ribosylation of alpha i subunits of Gi proteins indicated an impairment in liver membranes from cholestatic rats, whereas Western blotting for the detection of alpha i subunits showed decreased alpha i3 and increased alpha i2 levels in this condition. Further efforts are needed to better understand the molecular mechanisms underlying the relationship between the observed divergent expression of Gs and Gi proteins and liver cell proliferation in the cholestatic liver.
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PMID:G proteins in rat liver proliferation during cholestasis. 792 6

Administration of alpha-naphthylisothiocyanate (ANIT) to rats results in periportal cholangiolitic hepatopathy. Inflammation is a hallmark of the liver injury, and expression of toxicity is dependent on blood neutrophils. The role of other cellular mediators of inflammation in ANIT-induced hepatic insult is unknown. We hypothesized that platelets participate in the expression of ANIT hepatotoxicity. To test this, circulating platelets were decreased by administration of anti-rat platelet serum (PAb) prior to treatment of rats with ANIT. The PAb treatment regimen effectively reduced circulating thrombocytes over the course of the experiment. Twenty-four hours after oral ANIT administration, rats were euthanized and liver injury was estimated by increases in serum alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) activities. Cholestasis was assessed by measurement of serum total bilirubin concentration and bile flow. Reduction in platelet numbers was associated with attenuation of the increases in plasma ALT activity and bilirubin concentration seen after ANIT administration. However, PAb treatment did not attenuate the increase in plasma GGT, a marker of biliary epithelial cell injury. ANIT-induced changes in platelet function were assessed by evaluating platelet aggregation responses in platelet-rich plasma from rats treated with ANIT in vivo. ANIT treatment modestly decreased ex vivo platelet aggregation in response to ADP and collagen stimuli. To address further the role of platelet-derived cyclooxygenase products in ANIT hepatotoxicity, rats were treated with aspirin or ibuprofen. Neither pretreatment ameliorated ANIT-induced hepatic insult. These results suggest that platelets contribute to the expression of ANIT-induced liver injury, but they do not appear to act through the production of cyclooxygenase metabolites.
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PMID:Platelets and alpha-naphthylisothiocyanate-induced liver injury. 799 11

A reduced efficacy of VIP (43% of the control) without modification in its potency (ED50 = 2.2 nM) was observed in regenerating rat liver after cholestasis (bile duct ligation). The same occurred with glucagon-stimulated adenylyl cyclase activity because the efficacy of this VIP-related peptide was also reduced (53% of the control) without changes in its potency in this experimental model. The equilibrium binding data revealed no changes in either the affinity or the VIP binding capacity of liver membranes during cholestasis. Cross-linking experiments gave the same apparent molecular mass for the liver VIP-receptor complex (52 kDa) in control and cholestatic rats. The coupling between the VIP receptor and the Gs-protein was also unaffected because the sensitivity of VIP binding to GTP did not change after bile duct ligation. However, liver membranes from cholestatic rats showed a low extent of both ADP-ribosylation of the Gs-protein alpha subunit (as assessed with cholera toxin) and adenylyl cyclase stimulation by a direct effector such as forskolin. Thus, VIP-stimulated adenylyl cyclase activity is decreased in regenerating liver after cholestasis due probably to an impairment in the interaction between Gs-protein and adenylyl cyclase as well as a defect in the enzyme itself.
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PMID:VIP receptor/effector system in liver membranes from cholestatic rats. 800 39

Extracellular adenosine triphosphate (ATP) may regulate hepatocyte and cholangiocyte functions, and under some conditions it may have deleterious effects on bile secretion and cause cholestasis. The canalicular membrane enzyme Ca2+/Mg2+-ecto-ATPase (ecto-ATPase) hydrolyzes ATP/adenosine diphosphate (ATP/ADP) and regulates hepatic extracellular ATP concentration. Changes in liver ecto-ATPase in estrogen-induced cholestasis were examined in male rats receiving 17alpha-ethinylestradiol (E groups) for 1, 3, or 5 days (5 mg/kg/day, sc) and compared with changes in rats subjected to obstructive cholestasis (O groups) for 1, 3, or 8 days. Activity of ecto-ATPase, protein mass in canalicular membranes and bile (estimated by Western blotting), steady state mRNA levels (by Northern blotting), and cellular and acinar distributions of the enzyme (histochemistry and immunocytochemistry) were assessed in these groups. Activity of ecto-ATPase, protein mass in isolated canalicular membranes, and enzyme mRNA levels were significantly increased in E group rats as compared with controls. In contrast, these parameters were markedly decreased in O group rats, and the enzyme protein was undetectable in bile. The ecto-ATPase histochemical reaction was markedly increased in the canalicular membrane of E group rats, extending from acinar zone 2 to zone 1, whereas it decreased in the O group. The ecto-ATPase immunocytochemical reaction was present in the canalicular membrane and pericanalicular vesicles in control and E group hepatocytes, but it decreased in obstructive cholestasis and was localized only to the canalicular membrane. Thus, significant changes in liver ecto-ATPase were apparent in 17alpha-ethinylestradiol-induced cholestasis that were opposite to those observed in obstructive cholestasis. Assuming that the alterations observed in obstructive cholestasis are the result of the cholestatic phenomenon, we conclude that changes in ecto-ATPase in 17alpha-ethinylestradiol-treated rats might be either primary events or part of an adaptive response in 17alpha-ethinylestradiol-induced cholestasis.
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PMID:Differential expression of canalicular membrane Ca2+/Mg(2+)-ecto-ATPase in estrogen-induced and obstructive cholestasis in the rat. 1094 41

Cholestasis is a feature of many chronic human liver diseases. Previous studies pointed out an impairment of mitochondrial function as a cause of hepatocyte dysfunction leading to cholestatic liver injury. This study was aimed to evaluate liver mitochondrial bioenergetics of alpha-naphthylisothiocyanate-treated Wistar rats, an experimental model of cholestasis. Serum markers of liver injury and endogenous adenine nucleotides were measured. Changes in membrane potential, mitochondrial respiration, and alterations in mitochondrial permeability transition pore induction were monitored. In rats injected with alpha-naphthylisothiocyanate, liver injury with cholestasis developed within 48 h, as indicated by both serum enzyme activities and total bilirubin concentration. Liver mitochondria isolated from alpha-naphthylisothiocyanate-treated rats had a higher state 3 respiration, respiratory control ratio, ADP/O, and endogenous ATP/ADP ratio compared to controls. No change in state 4 respiration was observed. Associated with these parameters, cholestatic mitochondria exhibited an increased resistance to disruption of mitochondrial calcium homeostasis due to permeability transition pore induction. Hepatic mitochondria isolated from alpha-naphthylisothiocyanate-treated rats exhibited an improved efficiency. These data indicate that an adaptive response to resist cell death occurs during alpha-naphthylisothiocyanate-induced acute cholestasis.
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PMID:Improved efficiency of hepatic mitochondrial function in rats with cholestasis induced by an acute dose of alpha-naphthylisothiocyanate. 1212 59

Bleeding problems are associated with defects in platelet alpha-granules, yet little is known about how these granules are formed and released. Mutations affecting VPS33B, a novel Sec1/Munc18 protein, have recently been linked to arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome. We have characterized platelets from patients with ARC syndrome and observed reduced aggregation with arachidonate and adenosine diphosphate (ADP). Structural abnormalities seen in ARC platelets included increased platelet size, a pale appearance in blood films, elevated numbers of delta-granules, and completely absent alpha-granules. Soluble and membrane-bound alpha-granule proteins were significantly decreased or undetectable in ARC platelets, suggesting that both the releasable protein pools and membrane components of alpha-granules were absent. The role of VPS33B in platelet granule biogenesis was evaluated by immunofluorescence microscopy in normal human megakaryocytes. VPS33B colocalized appreciably with markers of alpha-granules, moderately with late endosomes/lysosomes, minimally with delta-granules/lysosomes, and not with cis-Golgi complexes. VPS33B protein expression determined by immunoblotting confirmed the presence of VPS33B in control fibroblasts but not in ARC fibroblasts, and in normal megakaryocytes but not in platelets. We conclude that like other Sec1/Munc18 proteins, VPS33B is involved in intracellular vesicle trafficking, being essential for the development of platelet alpha-granules but not for granule secretion.
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PMID:Requirement of VPS33B, a member of the Sec1/Munc18 protein family, in megakaryocyte and platelet alpha-granule biogenesis. 1612 20


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