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

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.

Loss of orphan receptor small heterodimer partner sensitizes mice to liver injury from obstructive cholestasis

“…6B), which is presumably due to the increased expression of Bsep, considered the primary driver of bile flow. 27 It is likely that this increased flow compensates for the increased Cyp7A1 levels and accounts for the normal hepatic bile acid levels in the Shp Ϫ/Ϫ mice. Previous results with ursodeoxycholic acidtreated Mdr2 Ϫ/Ϫ mice elegantly demonstrated that an increase in bile acid infarcts upon BDL was a consequence of increased bile flow and subsequently increased intraductal pressures.…”

Transporters involved in the hepatic uptake of 99mTc-mebrofenin and indocyanine green

“…Conjugated bile acids are predominantly transported by NTCP and it is therefore probable that bile salts inhibit the NTCP-mediated uptake of ICG during cholestasis. In addition, downregulation of uptake transporters during cholestasis may contribute to the 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 (30,(35)(36)(37). This differential response was confirmed in an in vivo rat model, which demonstrated that different stages of non-alcoholic fatty liver disease resulted in a differential decrease in several OATP and NTCP protein levels (38).…”

DNA methylation profile of tissue-dependent and differentially methylated regions (T-DMRs) in mouse promoter regions demonstrating tissue-specific gene expression

“…HNF1 affects the gene expression of HNF4a, and vice versa (Ktistaki and Talianidis 1997), and these factors, along with other liver-enriched transcription factors such as NR1H3 (LXR), NR1I2 (PXR), RXR, and PPAR␥, affect each other's expressions and functions (Geier et al 2007). D-REAM indicated that T-DMR is involved in the expression of these transcription factors, and that many genes with HNF-1A motifs and T-DMRs are specifically expressed in liver and kidney (Figs.…”