Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration
- 作者：Andreas Geier ; Martin Wagner ; Christoph G. Dietrich ; Michael Trauner
- 关键词：Cholestasis ; Liver regeneration ; Endotoxin ; Cytokines ; Nuclear (orphan) receptor ; Hepatocyte-enriched transcription factor
- 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Cell Research
- 出版年：2007
- 期刊代码：20_01674889
- 类别：bio
- 出版时间：March 2007
- 卷：1773
- 期：3
- 页码：283-308
- 文件大小：1286 K
摘要
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.