Transcriptional regulation of hepatobiliary transport systems in health and disease: Implications for a rationale approach to the treatment of intrahepatic cholestasis
Hepatobiliary transport systems mediate hepatic uptake and biliary excretion of bile acids, bilirubin and other biliary constituents. Hereditary or acquired defects of these transporters may cause or maintain cholestasis and jaundice under various clinical conditions including progressive familial i...
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| Format: | Article |
| Language: | English |
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Elsevier
2005-04-01
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| Series: | Annals of Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S166526811932071X |
| _version_ | 1818596653611876352 |
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| author | Martin Wagner Michael Trauner |
| author_facet | Martin Wagner Michael Trauner |
| author_sort | Martin Wagner |
| collection | DOAJ |
| description | Hepatobiliary transport systems mediate hepatic uptake and biliary excretion of bile acids, bilirubin and other biliary constituents. Hereditary or acquired defects of these transporters may cause or maintain cholestasis and jaundice under various clinical conditions including progressive familial intrahepatic cholestasis (PFIC) 1-3 or its milder forms, benign recurrent intrahepatic cholestasis (BRIC) 1 and 2, Dubin-Johnson syndrome, drug and inflammation-induced cholestasis and intrahepatic cholestasis of pregnancy. Moreover, induction of alternative efflux pumps for bile acids/bilirubin and phase I/II detoxifying enzymes may counteract hepatic accumulation of potentially toxic biliary constituents in cholestasis by providing alternative escape routes. Transcriptional and post-transcriptional regulation of hepatobiliary transporters in health and disease is mediated by multiple factors such as bile acids, proinflammatory cytokines, drugs and hormones. Ligand-activated nuclear receptors (NR) and hepatocyte-enriched transcription factors play a critical role in transcriptional transporter regulation. Many hepatobiliary transporter alterations in cholestatic liver disease can now be explained by ligand binding of accumulating cholephiles to NRs. Moreover, NRmediated actions may be targeted by pharmacological ligands. Understanding the transcriptional mechanisms leading to transporter changes therefore not only represents a key for understanding the pathophysiology of the cholestatic liver disease, but also represents a prerequisite for designing novel therapeutic strategies. |
| first_indexed | 2024-12-16T11:35:20Z |
| format | Article |
| id | doaj.art-8ef7a97975234ba3bd45ed597b49efe1 |
| institution | Directory Open Access Journal |
| issn | 1665-2681 |
| language | English |
| last_indexed | 2024-12-16T11:35:20Z |
| publishDate | 2005-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Annals of Hepatology |
| spelling | doaj.art-8ef7a97975234ba3bd45ed597b49efe12022-12-21T22:33:08ZengElsevierAnnals of Hepatology1665-26812005-04-01427799Transcriptional regulation of hepatobiliary transport systems in health and disease: Implications for a rationale approach to the treatment of intrahepatic cholestasisMartin Wagner0Michael Trauner1Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University Graz, AustriaLaboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University Graz, Austria; Address for correspondence:Hepatobiliary transport systems mediate hepatic uptake and biliary excretion of bile acids, bilirubin and other biliary constituents. Hereditary or acquired defects of these transporters may cause or maintain cholestasis and jaundice under various clinical conditions including progressive familial intrahepatic cholestasis (PFIC) 1-3 or its milder forms, benign recurrent intrahepatic cholestasis (BRIC) 1 and 2, Dubin-Johnson syndrome, drug and inflammation-induced cholestasis and intrahepatic cholestasis of pregnancy. Moreover, induction of alternative efflux pumps for bile acids/bilirubin and phase I/II detoxifying enzymes may counteract hepatic accumulation of potentially toxic biliary constituents in cholestasis by providing alternative escape routes. Transcriptional and post-transcriptional regulation of hepatobiliary transporters in health and disease is mediated by multiple factors such as bile acids, proinflammatory cytokines, drugs and hormones. Ligand-activated nuclear receptors (NR) and hepatocyte-enriched transcription factors play a critical role in transcriptional transporter regulation. Many hepatobiliary transporter alterations in cholestatic liver disease can now be explained by ligand binding of accumulating cholephiles to NRs. Moreover, NRmediated actions may be targeted by pharmacological ligands. Understanding the transcriptional mechanisms leading to transporter changes therefore not only represents a key for understanding the pathophysiology of the cholestatic liver disease, but also represents a prerequisite for designing novel therapeutic strategies.http://www.sciencedirect.com/science/article/pii/S166526811932071XBile formationbile acidshereditary and acquired cholestasishepatobiliary transportershepatocyte-enriched transcription factorsnuclear (orphan) receptors |
| spellingShingle | Martin Wagner Michael Trauner Transcriptional regulation of hepatobiliary transport systems in health and disease: Implications for a rationale approach to the treatment of intrahepatic cholestasis Annals of Hepatology Bile formation bile acids hereditary and acquired cholestasis hepatobiliary transporters hepatocyte-enriched transcription factors nuclear (orphan) receptors |
| title | Transcriptional regulation of hepatobiliary transport systems in health and disease: Implications for a rationale approach to the treatment of intrahepatic cholestasis |
| title_full | Transcriptional regulation of hepatobiliary transport systems in health and disease: Implications for a rationale approach to the treatment of intrahepatic cholestasis |
| title_fullStr | Transcriptional regulation of hepatobiliary transport systems in health and disease: Implications for a rationale approach to the treatment of intrahepatic cholestasis |
| title_full_unstemmed | Transcriptional regulation of hepatobiliary transport systems in health and disease: Implications for a rationale approach to the treatment of intrahepatic cholestasis |
| title_short | Transcriptional regulation of hepatobiliary transport systems in health and disease: Implications for a rationale approach to the treatment of intrahepatic cholestasis |
| title_sort | transcriptional regulation of hepatobiliary transport systems in health and disease implications for a rationale approach to the treatment of intrahepatic cholestasis |
| topic | Bile formation bile acids hereditary and acquired cholestasis hepatobiliary transporters hepatocyte-enriched transcription factors nuclear (orphan) receptors |
| url | http://www.sciencedirect.com/science/article/pii/S166526811932071X |
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