Genes and cholestasis

Jansen, Petér L. M.; Müller, Michael; Sturm, Ekkehard

doi:10.1053/jhep.2001.29625

Cited by 80 publications

(36 citation statements)

References 91 publications

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“…We first examined the expression of canalicular transporters BSEP and MDR2 that have been identified as the genes responsible for familial intrahepatic cholestasis (PFIC2 and PFIC3), respectively (30). Expression of BSEP was decreased in EE2-treated Wt ϩ/ϩ , Erb Ϫ/Ϫ , Fxr Ϫ/Ϫ , Pxr Ϫ/Ϫ , and Car Ϫ/Ϫ mice but was not altered in the EE2-treated Era Ϫ/Ϫ mice (Fig.…”

Section: Repression Of Bile Acid Transporters and Cholesterolmentioning

confidence: 99%

Estrogen Receptor α Mediates 17α-Ethynylestradiol Causing Hepatotoxicity

Yamamoto

Moore

Hess

et al. 2006

Journal of Biological Chemistry

159

114

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Estrogens are known to cause hepatotoxicity such as intrahepatic cholestasis in susceptible women during pregnancy, after administration of oral contraceptives, or during postmenopausal replacement therapy. Enterohepatic nuclear receptors including farnesoid X receptor (FXR), pregnane X receptor (PXR), and constitutive active/androstane receptor (CAR) are important in maintaining bile acid homeostasis and protecting the liver from bile acid toxicity. However, no nuclear receptor has been implicated in the mechanism for estrogen-induced hepatotoxicity. Here Era

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Section: Repression Of Bile Acid Transporters and Cholesterolmentioning

confidence: 99%

Estrogen Receptor α Mediates 17α-Ethynylestradiol Causing Hepatotoxicity

Yamamoto

Moore

Hess

et al. 2006

Journal of Biological Chemistry

159

114

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“…ABC transporters are favorite targets of reviewers. A treatise on all known ABC transporters is in the making (11); mammalian ABC transporters have been reviewed as a group (2); and there are numerous recent reviews on subfamilies of transporters (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) or individual transporters (24 -28, 28a). To avoid unproductive repetition, we focus here on some generalizations that could be useful to people outside this field of research, and on recent developments and controversies.…”

mentioning

confidence: 99%

Mammalian ABC Transporters in Health and Disease

Borst

Elferink

2002

Annu. Rev. Biochem.

1,413

1,152

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f Abstract The ATP-binding cassette (ABC) transporters are a family of large proteins in membranes and are able to transport a variety of compounds through membranes against steep concentration gradients at the cost of ATP hydrolysis. The available outline of the human genome contains 48 ABC genes; 16 of these have a known function and 14 are associated with a defined human disease. Major physiological functions of ABC transporters include the transport of lipids, bile salts, toxic compounds, and peptides for antigen presentation or other purposes. We review the functions of mammalian ABC transporters, emphasizing biochemical mechanisms and genetic defects. Our overview illustrates the importance of ABC transporters in human physiology, toxicology, pharmacology, and disease. We focus on three topics: (a) ABC transporters transporting drugs (xenotoxins) and drug conjugates. (b) Mammalian secretory epithelia using ABC transporters to excrete a large number of substances, sometimes against a steep concentration gradient. Several inborn errors in liver metabolism are due to mutations in one of the genes for these pumps; these are discussed. (c) A rapidly increasing number of ABC transporters are found to play a role in lipid transport. Defects in each of these transporters are involved in human inborn or acquired diseases.

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“…C hanges in the expression of hepatobiliary transporters provide a crucial mechanism to regulate bile acid homeostasis and to prevent hepatic bile acid toxicity in hepatocytes during cholestasis (1)(2)(3)(4)(5)(6)(7). The basolateral transporters, sodium-taurocholate cotransporting polypeptide (Ntcp; Slc10a1) and organic anion-transporting polypeptide (Oatp; Sl21a), are the major transporters for the uptake of bile acids and organic solutes from blood into the hepatocyte.…”

mentioning

confidence: 99%

Inflammation Mediated Down-Regulation of Hepatobiliary Transporters Contributes to Intrahepatic Cholestasis and Liver Damage in Murine Biliary Atresia

et al. 2009

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ABSTRACT:To investigate the hypothesis that during the development of biliary atresia, early changes in hepatobiliary transport are mainly related to the inflammatory process and lead to intrahepatic cholestasis and subsequent liver injury, livers from mice with rhesus rotavirus-induced biliary atresia were analyzed for mRNA expression of hepatobiliary transporters, nuclear receptors, and inflammatory cytokines. Seven days after inoculation, despite high bile acid concentrations in the liver, gene expression of canalicular and basolateral hepatobiliary transporters and their regulatory nuclear receptors was down-regulated with concomitant increase in gene expression of inflammatory cytokines and rise in serum unconjugated bilirubin. At 14 d, hepatobiliary transporters and nuclear receptors remained down-regulated although the inflammatory response subsided. The percentage of conjugated bilirubin started to increase as extrahepatic biliary obstruction occurred. At 18 d, expression of hepatobiliary transporters remained low, expression of nuclear receptors returned to normal, while expression of inflammatory cytokines decreased further. Moreover, histology demonstrated progressive inflammation, bile duct damage, ductular proliferation, and hepatocyte necrosis. In conclusion, intrahepatic cholestasis due to inflammation-related down-regulation of basolateral and canalicular hepatobiliary transporters is an early event in the development of biliary atresia. Intrahepatic cholestasis contributes to the development of jaundice and liver injury. (Pediatr Res 66: 380-385, 2009)

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Genes and cholestasis

Cited by 80 publications

References 91 publications

Estrogen Receptor α Mediates 17α-Ethynylestradiol Causing Hepatotoxicity

Estrogen Receptor α Mediates 17α-Ethynylestradiol Causing Hepatotoxicity

Mammalian ABC Transporters in Health and Disease

Inflammation Mediated Down-Regulation of Hepatobiliary Transporters Contributes to Intrahepatic Cholestasis and Liver Damage in Murine Biliary Atresia

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