Review
Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration

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Abstract

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.

Abbreviations

ABC
ATP-binding cassette
CAR (NR1I3)
constitutive androstane receptor
CBDL
common bile duct ligation
Cyp
cytochrome p450
FXR (NR1H4)
farnesoid X receptor/bile acid receptor
HNF
Hepatocyte nuclear factor
IL-1β
interleukin 1 beta
LPS
lipopolysaccharide
Mdr
multidrug resistance gene
Mrp
multidrug resistance-associated protein
Ntcp (Slc10a1)
Na+/taurocholate cotransporter
Oatp (Slc21a)
organic anion transporter
Ost
organic solute transporter
PPARα (NR1C1)
peroxisome proliferator activated receptor alpha
PPARγ (NR1C3)
peroxisome proliferator activated receptor gamma
PXR (NR1I2)
pregnane X receptor
RARα (NR1B1)
retinoic acid receptor
RXRα (NR2B1)
retinoid X receptor
SHP (NR0B2)
short heterodimer partner
TNFα
tumor necrosis factor alpha

Keywords

Cholestasis
Liver regeneration
Endotoxin
Cytokines
Nuclear (orphan) receptor
Hepatocyte-enriched transcription factor

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