Table 1.
Nuclear receptors as therapeutic targets in cholestasis
| NR | Ligands | Therapeutic | Target Genes | Therapeutic Effects |
|---|---|---|---|---|
| FXR (NR1H4) | CDCA, DCA, CA, synthetic: GW4064, 6-ECDCA | Synthesis: | Indirect repressive effects via SHP | Repression of bile acid synthesis indirectly via SHP |
| Detoxification: | CYP3A4, SULT2A1, UGT2B4, UGT2B7 | Induction of bile acid detoxification | ||
| Transport: | MRP2/Mrp2, OATP1B3, OSTα/β, SHP, BSEP/Bsep, I-BABP; MDR3/Mdr2 indirect repressive effects via SHP | Induction of canalicular and alternative basolateral bile acid excretion Increase in bile flow Increase in bililary phospholipid content Repression of bile acid uptake (effect may be restricted to rodents) | ||
| Fibrosis: | SHP, PPARγ | Indirect antifibrotic activity via SHP and PPARγ. | ||
| SHP (NR0B2) | No ligand, FXR target | Synthesis: | CYP7A1/Cyp7a1, CYP8B1/Cyp8b1, CYP27A1 | Repression of bile acid synthesis |
| Transport: | Ntcp, ASBT/Asbt | Repression of hepatic and intestinal bile acid uptake | ||
| Fibrosis: | α1(l)collagen | Induction of quiescent HSC phenotype, increase in HSC apoptosis | ||
| PXR (NR1/2) | Rifampicin in humans, phenobarbital, dexamethasone, statins, St. John's wort, clotrimazole pregnenolone-16α-carbonitrile (PCN) in rodents | Synthesis: | CYP7A1 | Indirect repression (via interaction with HNF4α) of CYP7A1 in vitro |
| Detoxification: | CYP3A4, SULT2A1/Sult2a1, UGT1A1 | Induction of phase I and II bile acid and bilirubin detoxification systems | ||
| Transport: | MRP2/Mrp2, MRP3, Oatp1a4, MDR1 | Induction of orthograde canalicular and alternative basolateral bile acid excretion | ||
| Fibrosis: | Antifibrotic activities, inhibition of HSC transdifferentiation | |||
| CAR (NR1/3)* | Yin Chin, CITCO, bilirubin, Phenobarbital, 1,4-bis-[2-(3,5-ichlorpyidyloxy)] benzene (TCPOBOP), dimethoxycoumarin, dimethylesculetin | Detoxification: | CYP3A4, Sult2a1, UGT1A1 | Induction of bile acid and bilirubin detoxification systems |
| Transport: | MRP2/Mrp2, Mrp3, MRP4/Mrp4 | Induction of orthograde canalicular and alternative basolateral bile acid excretion Minor increase in bile flow | ||
| VDR (NR1/1) | 1α,25-dihydroxy-vitamin, D3, LCA | Detoxification: | CYP3A4/Cyp3a11, SULT2A1/Sult2a1 | Induction of bile acid detoxification systems |
| Transport: | Mrp3, ASBT | Induction of alternative basolateral bile acid excretion and induction of of biliary and intestinal bile acid reabsorption | ||
| NRs: | FXR | Inhibition of FXR transactivation | ||
| HNF4α (NR2A1) | Fatty acyl-coenzyme A thioesters | Synthesis: | Cyp7a1, CYP8B1/Cyp8b1, CYP27A1 | Reduced HNF4α binding or expression down-regulates bile acid synthesis and detoxification pathways |
| Detoxification: | CYP3A4, Cyp3, SULT2A1 | |||
| Transport: | ASBT, OATP1B1, Oatp1a1, Oatp1b2, Oatp1a4, Ntcp | Required for constitutive expression of various basolateral uptake systems | ||
| NRs, Transcription factors | PXR, CAR, HNF1α | Indirect regulation of PXR, CAR and HNF1α target genes | ||
| LRH-1 (NR5A2) | Phospholipids | Synthesis: | CYP7A1, CYP8B1/Cyp8b1 | Required for basal expression of bile acid |
| Transport | MRP3, Asbt, Ntcp, Bsep, Mdr2 | synthesis enzymes, transporters and NRs | ||
| NRs: | FXR, SHP | |||
| PPARα (NR1C1) | Fatty acids, fibrates, statins, eicasaonoids, leukotriens, NSAIDs, WY-14643 | Synthesis: | CYP7A1 | Repression of bile acid synthesis |
| Detoxification: | SULT2A1, UGT2B4, UGT1A3 | Induction of bile acid detoxification systems | ||
| Transporti: | Mdr2, ASBT | Protection of bile duct epithelium via increased phospholipid secretion and increased bile acid reabsorption | ||
| NRs: | FXR | Indirect induction of FXR targets such as UGT2B4 | ||
| PPARγ (NR1C3) | thiazolidinediones (glitazones) | NRs: | SHP | Effects on SHP targets? |
| Fibrosis: | α1(l)collagen | Inhibits HSC activation | ||
| General | Attenuation of the inflammatory response, senzitation to insulin | |||
| LXRα (NR1H3) | Oxysterols, fatty acids, 6α-hydroxylated bile acids, TO1317 | Synthesis: | Cyp7a1/CYP7A1 | Induction of rodent Cyp7a1, repression of human CYP7A1 |
| Detoxification: | Sult2a9, UGT1A3 | Induction of bile acid sulfation and glucuronidation | ||
| Transport: | Mrp4 | Induction of alternative basolateral bile acid excretion | ||
| GR (NR3C1) | Glucocorticoids, potentially UDCA | Transport: | ASBT, NTCP, potentially AE2, Bsep, Mrp2 | Contribution of effects on transporters to anti-inflammatory properties in treatement of inflammatory cholestasis (“steroid whitewash”) |
| NRs: | CAR, PXR, RXRα | Potentiates action of PXR and CAR |
*
Please note that CAR can be activated either indirectly or directly by ligand binding (e.g. TCPOBOP (Goodwin et al. 2004).