Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

The occurrence of cholestasis during pregnancy may be due to several disorders. These include pregnancyspecific diseases, like intrahepatic cholestasis of pregnancy(ICP), as well as to other causes such as oligosymptomatic choledocolitiasis, viral hepatitis and other underlying liver disorders like primary biliary cirrhosis. In recent years, the discovery of mutations in hepatobiliary transporters genes responsible of some rare forms of genetic cholestasis have led to the study of this mutations in pregnant women with cholestasis. Thus, mutations in the hepatic phospholipid transporter(MDR3, ABCB4), in the aminophospholipid transporter ATP8B1 and in the bile salt export pump (BSEP, ABCB11) have been found in patients diagnosed as ICP. However, patients included in these studies belong to a heterogeneous population, which may not represent true cases of ICP since some reports include patients diagnosed in the first trimester of pregnancy, with elevated serum levels of gamma-glutamyl transpeptidase and clear evidence of chronic liver disease. Thus, consideration must be given to the possibility of other rare underlying hepatic disorders may be unmasked during pregnancy with cholestasis as its first manifestation.
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PMID:Cholestasis during pregnancy: rare hepatic diseases unmasked by pregnancy. 1706 Aug 87

Estrogens cause intrahepatic cholestasis in susceptible women during pregnancy, after administration of oral contraceptives, or during postmenopausal hormone replacement therapy. 17alpha-Ethinylestradiol (EE) is a synthetic estrogen widely used to cause experimental cholestasis in rodents with the aim of examining molecular mechanisms involved in this disease. EE actions on the liver are thought to be mediated by estrogen receptor alpha (ERalpha) and pituitary hormones. We tested this hypothesis by analyzing metabolic changes induced by EE in livers from hypophysectomized (HYPOX) and hypothyroid rats. Microarray studies revealed that the number of genes regulated by EE was increased almost 4-fold in HYPOX rat livers compared with intact males. Little overlap was apparent between the effects of EE in intact and HYPOX rats, demonstrating that pituitary hormones play a critical role in the hepatic effects of EE. Consistently, hypophysectomy protects the liver against induction by EE of serum bilirubin and alkaline phosphatase, two markers of cholestasis and hepatotoxicity and modulates the effects of EE on several genes involved in bile acid homeostasis (e.g., FXR, SHP, BSEP, and Cyp8b1). Finally, we demonstrate a novel mechanism of action of EE through binding and negative regulation of glucocorticoid receptor-mediated transcription. In summary, pituitary- and ERalpha-independent mechanisms contribute to development of EE-induced changes in liver transcriptome. Such mechanisms may be relevant when this model of EE-induced cholestasis is evaluated. The observation that the pharmacological effects of estrogen in liver differ in the absence or presence of the pituitary could be clinically relevant, because different drugs that block actions of pituitary hormones are now available.
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PMID:Role of pituitary hormones on 17alpha-ethinylestradiol-induced cholestasis in rat. 1710 34

Hepatic uptake and biliary excretion of organic anions (e.g., bile acids and bilirubin) is mediated by hepatobiliary transport systems. Defects in transporter expression and function can cause or maintain cholestasis and jaundice. Recruitment of alternative export transporters in coordination with phase I and II detoxifying pathways provides alternative pathways to counteract accumulation of potentially toxic biliary constituents in cholestasis. The genes encoding for organic anion uptake (NTCP, OATPs), canalicular export (BSEP, MRP2) and alternative basolateral export (MRP3, MRP4) in liver are regulated by a complex interacting network of hepatocyte nuclear factors (HNF1, 3, 4) and nuclear (orphan) receptors (e.g., FXR, PXR, CAR, RAR, LRH-1, SHP, GR). Bile acids, proinflammatory cytokines, hormones and drugs mediate causative and adaptive transporter changes at a transcriptional level by interacting with these nuclear factors and receptors. Unraveling the underlying regulatory mechanisms may therefore not only allow a better understanding of the molecular pathophysiology of cholestatic liver diseases but should also identify potential pharmacological strategies targeting these regulatory networks. This review is focused on general principles of transcriptional basolateral and canalicular transporter regulation in inflammation-induced cholestasis, ethinylestradiol- and pregnancy-associated cholestasis, obstructive cholestasis and liver regeneration. Moreover, the potential therapeutic role of nuclear receptor agonists for the management of liver diseases is highlighted.
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PMID:Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration. 1729 2

Primary metabolic disorders are a disparate group of diseases that may or may not be accompanied by hepatic manifestations. Those with liver involvement may show a range of histopathologic changes. Proper histologic diagnosis requires correlation with clinical and laboratory data, including evaluation for mutations either via serum protein electrophoresis or through formal genetic analysis. This article is a review of the three most common inherited metabolic disorders which may present with a hepatitic pattern. In alpha1-antitrypsin disorder, there is a broad range of clinical presentations, age at presentation, and histological features ranging from "neonatal hepatitis" to a chronic progressive hepatitis in later childhood and adulthood. Hence, this disorder must be in the differential diagnosis of liver disease of the very young, and in older children and adults, with or without coexistent overt pulmonary symptoms. In Wilson disease, presentation tends to be in older childhood or the adult, with a progressive chronic hepatitis. Cystic fibrosis may feature a characteristic obstructive biliary syndrome, coexisting with the many extrahepatic manifestations of this debilitating disease. Lastly, the progressive familial intrahepatic cholestasis (PFIC) syndromes are given as examples of inherited metabolic conditions in which relentlessly progressive cholestatic liver disease eventuates over years in end-stage cholestatic liver disease with cirrhosis. Distinguishing features include absence of elevated serum gamma-glutamyl transpeptidase (GGT) in PFIC-1 and PFIC-2, and elevated GGT in PFIC-3. However, molecular studies are required for a confident diagnosis of the rare PFIC syndromes.
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PMID:Hepatitic inherited metabolic disorders. 1735 91

The non-steroidal antiandrogen flutamide is widely used for treatment of prostatic cancer, but causes side effects, including cholestatic hepatitis and fulminant hepatitis. We investigated the pathogenesis of flutamide-induced cholestatic hepatitis, focusing on the bile salt export pump (BSEP; ABCB11), which exports bile salts to the bile. We examined the inhibitory effects of flutamide and its active metabolite, hydroxyflutamide, on the transport of taurocholic acid (TCA) by membrane vesicles derived from hBSEP-expressing Sf9 cells. Flutamide inhibited the transport of TCA by hBSEP (IC50 value, about 50 microM), while hydroxyflutamide had no effect at up to 100 microM. When flutamide was administered to rats as a single oral dose of 100 mg/kg, the biliary excretion rate of bolus-injected [3H]TCA was decreased and the liver tissue concentration of flutamide exceeded 50 microM. Repeated doses of flutamide for 5 d (10 mg/kg/d) also decreased the biliary excretion rate of bolus-injected [3H]TCA. In this case, the liver tissue concentration of flutamide was below 0.1 microM. In both cases, no change in the mRNA level of rat Bsep was detected by RT-PCR. These results suggest that flutamide itself, but not its major metabolite, may cause cholestasis by inhibiting BSEP-mediated bile salt excretion.
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PMID:Involvement of bile salt export pump in flutamide-induced cholestatic hepatitis. 1740 13

Phytosterols, components of soy-derived lipids, are among the proposed exacerbants of parenteral nutrition-associated cholestasis (PNAC). We investigated whether phytosterols contribute to bile acid (BA)-induced hepatocyte damage by antagonizing a nuclear receptor (NR) critically involved in hepatoprotection from cholestasis, FXR (farnesoid X receptor, NR1H4). In HepG2 cells, stigmasterol acetate (StigAc), a water-soluble Stig derivative, suppressed ligand-activated expression of FXR target genes involved in adaptation to cholestasis (i.e. BSEP, FGF-19, OSTalpha/beta). Furthermore, StigAc antagonized BA-activated, FXR target genes SHP and BSEP in FXR+/+, but not in FXR-/- mouse hepatocytes. Both Stig and StigAc inhibited BA-activated, FXR-dependent reporter gene expression in transfected HepG2 cells, whereas the most prevalent phytosterol in lipids, beta-sitosterol, had no inhibitory effect. Finally, among six ligand-activated NR-ligand binding domains (LBDs) tested, antagonism by StigAc was specific to only two (FXR and PXR, pregnane X receptor, NR1I2). We demonstrate that Stig, a phytosterol prevalent in soy-derived PN lipid solutions, is a potent in vitro antagonist of the NR for bile acids FXR.
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PMID:Stigmasterol, a soy lipid-derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR. 1762 54

Human BSEP (ABCB11) mutations are the molecular basis for at least three clinical forms of liver disease, progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2), and intrahepatic cholestasis of pregnancy (ICP). To better understand the pathobiology of these disease phenotypes, we hypothesized that different mutations may cause significant differences in protein defects. Therefore we compared the effect of two PFIC2 mutations (D482G, E297G) with two BRIC2 mutations (A570T and R1050C) and one ICP mutation (N591S) with regard to the subcellular localization, maturation, and function of the rat Bsep protein. Bile salt transport was retained in all but the E297G mutant. Mutant proteins were expressed at reduced levels on the plasma membrane of transfected HEK293 cells compared with wild-type (WT) Bsep in the following order: WT > N591S > R1050C approximately A570T approximately E297G >> D482G. Total cell protein and surface protein expression were reduced to the same extent, suggesting that trafficking of these mutants to the plasma membrane is not impaired. All Bsep mutants accumulate in perinuclear aggresome-like structures in the presence of the proteasome inhibitor MG-132, suggesting that mutations are associated with protein instability and ubiquitin-dependent degradation. Reduced temperature, sodium butyrate, and sodium 4-phenylbutyrate enhanced the expression of the mature and cell surface D482G protein in HEK293 cells. These results suggest that the clinical phenotypes of PFIC2, BRIC2, and ICP may directly correlate with the amount of mature protein that is expressed at the cell surface and that strategies to stabilize cell surface mutant protein may be therapeutic.
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PMID:Levels of plasma membrane expression in progressive and benign mutations of the bile salt export pump (Bsep/Abcb11) correlate with severity of cholestatic diseases. 1785 69

Progressive familial cholestasis (PFIC) 2 and benign recurrent intrahepatic cholestasis (BRIC) 2 are caused by mutations in the bile salt export pump (BSEP, ABCB11) gene; however, their prognosis differs. PFIC2 progresses to cirrhosis and requires liver transplantation, whereas BRIC2 is clinically benign. To identify the molecular mechanism(s) responsible for the phenotypic differences, eight PFIC2 and two BRIC2 mutations were introduced in rat Bsep, which was transfected in MDCK II cells. Taurocholate transport activity, protein expression, and subcellular distribution of these mutant proteins were studied in a polarized MDCK II monolayer. The taurocholate transport activity was approximately half of the wild-type (WT) in BRIC2 mutants (A570T and R1050C), was substantially less in two PFIC2 mutants (D482G and E297G), and was almost abolished in six other PFIC2 mutants (K461E, G982R, R1153C, R1268Q, 3767-3768insC, and R1057X). Bsep protein expression levels correlated closely with transport activity, except for R1057X. The half-life of the D482G mutant was shorter than that of the WT (1.35 h vs. 3.49 h in the mature form). BRIC2 mutants and three PFIC mutants (D482G, E297G, and R1057X) were predominantly distributed in the apical membrane. The other PFIC2 mutants remained intracellular. The R1057X mutant protein was stably expressed and trafficked to the apical membrane, suggesting that the COOH-terminal tail is required for transport activity but not for correct targeting. In conclusion, taurocholate transport function was impaired in proportion to rapid degradation of Bsep protein in the mutants, which were aligned in the following order: A570T and R1050C > D482G > E297G > K461E, G982R, R1153C, R1268Q, 3767-3768insC, and R1057X. These results may explain the phenotypic difference between BRIC2 and PFIC2.
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PMID:Phenotypic differences in PFIC2 and BRIC2 correlate with protein stability of mutant Bsep and impaired taurocholate secretion in MDCK II cells. 1794 49

To investigate how the liver adapts to chronic obstructive cholestasis, liver samples from infants with early- and late-stage cholestasis were analyzed for changes in the levels of hepatocyte transporters and nuclear receptors. At early-stage cholestasis, most canalicular transporters and sinusoidal uptake transporters were downregulated, including bile salt export pump (BSEP, ABCB11), multidrug resistant protein 3 (MDR3, ABCB4), multidrug-resistant associated protein 2 (MRP2, ABCC2), sodium-dependent taurocholate cotransporting polypeptide (NTCP, SLC10A1), organic anion transporter (OATP, SLCO1A2), and nuclear receptor farnesoid X receptor (FXR, NR1H4). At late-stage cholestasis, FXR-BSEP levels returned to normal, MDR3 and MDR1 (ABCB1) were upregulated, and MRP-2 was downregulated. In addition, alternative sinusoidal efflux transporters, organic solute transporter alpha/beta (OSTalpha/beta) and MRP4 were upregulated, and pregnane X receptor (PXR, NR1I2) levels decreased. Cytochrome enzyme P450 7A1 was markedly downregulated at both early and late-stage cholestasis. An analysis of the long-term prognosis of 18 patients revealed lower PXR and constitutive androstane receptor (CAR, NR1I3) levels in the poor prognosis group. In conclusion, at long-term cholestasis, hepatocyte bile efflux was through sinusoidal and canalicular transporters, with FXR-BSEP levels maintained and PXR downregulated. Low PXR and CAR levels were associated with poor prognosis.
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PMID:Expression of hepatocyte transporters and nuclear receptors in children with early and late-stage biliary atresia. 1832 54

The bile salt export pump (Bsep) represents the major bile salt transport system at the canalicular membrane of hepatocytes. When examined in model cell lines, genetic mutations in the BSEP gene impair its targeting and transport function, contributing to the pathogenesis of progressive familial intrahepatic cholestasis type II (PFIC II). PFIC II mutations are known to lead to a deficiency of BSEP in human hepatocytes, suggesting that PFIC II mutants are unstable and degraded in the cell. To investigate this further, we have characterized the impact of several PFIC II mutations on the processing and stability of rat Bsep. G238V, D482G, G982R, R1153C, and R1286Q all retain Bsep to the endoplasmic reticulum (ER) to different extents. Except for R1153C, the PFIC II mutants are degraded with varying half-lives. G238V and D482G are partially misfolded and can be stabilized by low temperature and glycerol. The proteasome provides the major degradation pathway for the PFIC II mutants, whereas the lysosome also contributes to the degradation of D482G. The PFIC II mutants appear to be more heavily ubiquitinated compared with the wild-type (wt) Bsep, and their ubiquitination is increased by the proteasome inhibitors. Overexpression of several E3 ubiquitin ligases, which are involved in ER-associated degradation (ERAD), lead to the decrease of both mutant and wt Bsep. Gene knockdown studies showed that the ERAD E3s Rma1 and TEB4 contribute to the degradation of G238V, whereas HRD1 contributes to the degradation of a mutant lacking the lumenal glycosylation domain (DeltaGly). Furthermore, we present evidence that G982R weakly associates with various components of the ER quality control system. These data together demonstrate that the PFIC II mutants except R1153C and DeltaGly are degraded by the ERAD pathway.
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PMID:Degradation of the bile salt export pump at endoplasmic reticulum in progressive familial intrahepatic cholestasis type II. 1879 35


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