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)

ATP-dependent transport of biliary constituents, such as bile acids, reduced glutathione, and bilirubin glucuronosides across the hepatocyte canalicular membrane into bile represents the decisive driving force for the formation of biliary fluid. Functional characterization, cloning, and localization of hepatocellular transporter proteins has provided a molecular understanding of the mechanisms underlying bile flow and intrahepatic cholestasis. Genetic variants in humans and genetic knockout in rodents, or transporter inhibition have indicated that both the conjugate export pump MRP2 (multidrug resistance protein 2; ABCC2) and the bile salt export pump BSEP (ABCB11) are major contributors to bile acid-independent and bile acid-dependent bile flow, respectively. In humans, genetic variants of BSEP, leading to an impaired transport activity or localization of the protein in the canalicular membrane, are associated with severe intrahepatic cholestasis. Efflux pumps of the basolateral hepatocyte membrane, particularly MRP3 (multidrug resistance protein 3; ABCC3) and MRP4 (multidrug resistance protein 4; ABCC4) pump substances from hepatocytes into sinusoidal blood. These efflux pumps have been recognized in recent years to play an important compensatory role in cholestasis and to contribute to the balance between uptake and efflux of substances during the vectorial transport from sinusoidal blood into bile. This sinusoidal efflux not only enables subsequent renal elimination, but also re-uptake of substances into neighboring and more centrally located hepatocytes in the sinusoid.
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PMID:Cholestasis and the role of basolateral efflux pumps. 2213 80

We describe a child with progressive familial intrahepatic cholestasis (PFIC) of type 2 inherited as uniparental isodisomy of chromosome 2. Bile salt export pump (BSEP) deficiency is a severe, genetically determined subtype PFIC caused by mutations in ABCB11, the gene encoding a bile salt transporter protein. Clinical and pathological diagnosis in PFIC2 is corroborated by an ample array of ABCB11 mutations, inherited in an autosomal recessive fashion. We report clinical, pathological, and molecular studies in a child with PFIC2. A 5.5-year-old boy harbored a described pathogenic mutation (p.R832C) in ABCB11. The mutation was found to be homozygous in the patient and heterozygous in DNA from paternal, but not maternal blood. Having ruled out maternal gene deletion and somatic mosaicism, we showed that the child had inherited an isodisomic paternal chromosome 2, including the 2q31.1 region where ABCB11 is located. The present report is the first description of uniparental isodisomy in a hepatic heritable disorder. Recognizing isodisomic transmission may have a significant impact on genetic counseling helping to define the risk of recurrence in subsequent pregnancies.
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PMID:Paternal isodisomy of chromosome 2 in a child with bile salt export pump deficiency. 2236 1

Progressive familial intrahepatic cholestasis (PFIC), types 1, 2 and 3, are due to defects in genes involved in bile secretion (FIC1, BSEP, MDR3). PFIC and inborn errors of bile acid synthesis (IEBAS) often present in infancy with cholestasis. The distinctive feature of PFIC 1 and 2 and IEBAS is a normal level of GGT, while IEBAS are suspected in patients with low plasma bile acids concentration. Molecular testing, urinary bile acid analysis (IEBAS), liver biopsy and immuno-staining are used for the diagnosis. Some patients with PFIC can be successfully treated with ursodeoxycholic acid or partial external biliary diversion. IEBAS is treated with cholic acid. Liver transplantation is required for cirrhosis with liver failure. Hepatocarcinoma has been reported in PFIC2.
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PMID:Progressive familial intrahepatic cholestasis and inborn errors of bile acid synthesis. 2260 95

Bile salts, cholesterol and phosphatidylcholine are secreted across the canalicular membrane of hepatocytes into bile by ATP-binding cassette (ABC) transporters. Secretion of bile salts by ABCB11 is essential for bile flow and for absorption of lipids and fat-soluble vitamins. ABCG5 and ABCG8 eliminate excess cholesterol and sterols from the body by secreting them into bile. There are two mechanisms to protect the canalicular membrane from solubilization by bile salts; ABCB4 secretes phosphatidylcholine into bile to form mixed micelles with bile salts, and ATP8B1 maintains the canalicular membrane in a liquid-ordered state. Three different forms of progressive familial intrahepatic cholestasis (PFIC) disorders, PFIC1, PFIC2 and PFIC3, are caused by mutations in ATP8B1, ABCB11 and ABCB4, respectively. Sitosterolemia is caused by mutations in ABCG5 and ABCG8. This article reviews the physiological roles of these canalicular transporters, and the pathophysiological processes and clinical features associated with their mutations.
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PMID:Hepatobiliary transport in health and disease. 2285 19

Miroestrol and deoxymiroestrol are highly active phytoestrogens isolated from the tuberous root of Pueraria candollei var. mirifica (Leguminosae). Modulatory effects of miroestrol and deoxymiroestrol on the mRNAs of BSEP and MRP2 genes involved in bile salt transportation, in C57BL/6 mice were investigated. In contrast to estradiol, miroestrol and deoxymiroestrol suppressed the expression of BSEP and MRP2 mRNA in both male and female mice. The results suggest for the first time that the use of miroestrol and deoxymiroestrol-containing products as alternative medicines or health supplements should be concerned according to their effects on key genes that regulate the bile salt export pump, which could result in the risk of hepatotoxicity and intrahepatic cholestasis.
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PMID:Suppression of BSEP and MRP2 in mouse liver by miroestrol and deoxymiroestrol isolated from Pueraria candollei. 2301 71

Progressive familial intrahepatic cholestasis (PFIC) refers to a heterogeneous group of autosomal-recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. The exact prevalence remains unknown, but the estimated incidence varies between 1/50,000 and 1/100,000 births. Three types of PFIC have been identified and associated with mutations in hepatocellular transport-system genes involved in bile formation. PFIC1 and PFIC2 usually appear in the first months of life, whereas onset of PFIC3 may arise later in infancy, in childhood or even during young adulthood. The main clinical manifestations include cholestasis, pruritus and jaundice. PFIC patients usually develop fibrosis and end-stage liver disease before adulthood. Serum gamma-glutamyltransferase (GGT) activity is normal in PFIC1 and PFIC2 patients, but is elevated in PFIC3 patients. Both PFIC1 and PFIC2 are caused by impaired bile salt secretion due to defects in ATP8B1 encoding the FIC1 protein and in ABCB11 encoding bile salt export pump (BSEP) protein, respectively. Defects in ABCB4, encoding multidrug resistance 3 protein (MDR3), impair biliary phospholipid secretion, resulting in PFIC3. Diagnosis is based on clinical manifestations, liver ultrasonography, cholangiography and liver histology, as well as on specific tests to exclude other causes of childhood cholestasis. MDR3 and BSEP liver immunostaining, and analysis of biliary lipid composition should help to select PFIC candidates for whom genotyping could be proposed to confirm the diagnosis. Antenatal diagnosis may be proposed for affected families in which a mutation has been identified. Ursodeoxycholic acid (UDCA) therapy should be initiated in all patients to prevent liver damage. In some PFIC1 and PFIC2 patients, biliary diversion may also relieve pruritus and slow disease progression. However, most PFIC patients are ultimately candidates for liver transplantation. Monitoring of liver tumors, especially in PFIC2 patients, should be offered from the first year of life. Hepatocyte transplantation, gene therapy and specific targeted pharmacotherapy may represent alternative treatments in the future.
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PMID:Progressive familial intrahepatic cholestasis. 2314 90

The International Transporter Consortium (ITC) has recently described seven transporters of particular relevance to drug development. Based on the second ITC transporter workshop in 2012, we have identified additional transporters of emerging importance in pharmacokinetics, interference of drugs with transport of endogenous compounds, and drug-drug interactions (DDIs) in humans. The multidrug and toxin extrusion proteins (MATEs, gene symbol SLC47A) mediate excretion of organic cations into bile and urine. MATEs are important in renal DDIs. Multidrug resistance proteins (MRPs or ABCCs) are drug and conjugate efflux pumps, and impaired activity of MRP2 results in conjugated hyperbilirubinemia. The bile salt export pump (BSEP or ABCB11) prevents accumulation of toxic bile salt concentrations in hepatocytes, and BSEP inhibition or deficiency may cause cholestasis and liver injury. In addition, examples are presented on the roles of nucleoside and peptide transporters in drug targeting and disposition.
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PMID:Emerging transporters of clinical importance: an update from the International Transporter Consortium. 2358 5

The bile salt export pump (BSEP, ABCB11) is the primary transporter of bile acids from the hepatocyte to the biliary system. This rate-limiting step in bile formation is essential to the formation of bile salt dependent bile flow, the enterohepatic circulation of bile acids, and the digestion of dietary fats. Mutations in BSEP are associated with cholestatic diseases such as progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2), drug-induced cholestasis, and intrahepatic cholestasis of pregnancy. Development of clinical therapies for these conditions necessitates a clear understanding of the cell biology of biosynthesis, trafficking, and transcriptional and translational regulation of BSEP. This chapter will focus on the molecular and cell biological aspects of this critical hepatic membrane transporter.
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PMID:Biosynthesis and trafficking of the bile salt export pump, BSEP: therapeutic implications of BSEP mutations. 2368 87

Bile salt export pump (BSEP/ABCB11), a member of the family of ATP-binding cassette transporters, is localized on the canalicular membrane of hepatocytes and mediates the efficient biliary excretion of bile acid. The secretion of bile acid into bile by BSEP provides the primary osmotic driving force for bile flow generation. Intrahepatic cholestasis resulting from dysfunction of BSEP can be caused by a mutation in the gene encoding this protein or by acquired factors, such as the side effects of xenobiotics and drugs. In some pathophysiological states, inhibition of BSEP function is associated with its reduced expression on the canalicular membrane caused by impaired trafficking and sorting of BSEP. This fact has generated interest in better understanding the trafficking and sorting mechanism of BSEP. This review describes the molecular characteristics and physiological roles of BSEP, the trafficking and sorting machinery of BSEP, and the mechanisms responsible for disturbance of BSEP, which causes intrahepatic cholestasis.
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PMID:Bile salt export pump (BSEP/ABCB11): trafficking and sorting disturbances. 2387 51

Parenteral nutrition-associated liver disease (PNALD) is a serious complication of PN in infants who do not tolerate enteral feedings, especially those with acquired or congenital intestinal diseases. Yet, the mechanisms underlying PNALD are poorly understood. It has been suggested that a component of soy oil (SO) lipid emulsions in PN solutions, such as plant sterols (phytosterols), may be responsible for PNALD, and that use of fish oil (FO)-based lipid emulsions may be protective. We used a mouse model of PNALD combining PN infusion with intestinal injury to demonstrate that SO-based PN solution causes liver damage and hepatic macrophage activation and that PN solutions that are FO-based or devoid of all lipids prevent these processes. We have furthermore demonstrated that a factor in the SO lipid emulsions, stigmasterol, promotes cholestasis, liver injury, and liver macrophage activation in this model and that this effect may be mediated through suppression of canalicular bile transporter expression (Abcb11/BSEP, Abcc2/MRP2) via antagonism of the nuclear receptors Fxr and Lxr, and failure of up-regulation of the hepatic sterol exporters (Abcg5/g8/ABCG5/8). This study provides experimental evidence that plant sterols in lipid emulsions are a major factor responsible for PNALD and that the absence or reduction of plant sterols is one of the mechanisms for hepatic protection in infants receiving FO-based PN or lipid minimization PN treatment. Modification of lipid constituents in PN solutions is thus a promising strategy to reduce incidence and severity of PNALD.
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PMID:Phytosterols promote liver injury and Kupffer cell activation in parenteral nutrition-associated liver disease. 2414 79


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