1. Nuclear receptor regulation of hepatic function
Saul J. Karpen 
Journal of Hepatology 
Volume 36, Issue 6, Pages (June 2002)
DOI: /S (02)

2. Fig. 1
Nuclear receptor domains and DNA-binding elements. (A) Representation of the functional domains of nuclear receptors. (B) Depiction of the Class II NR family members discussed in this review. (C) Binding site designations. Note that there can be significant variability in the canonical AGGTCA hexamer sequence, and that surrounding and intervening DNA sequences may significantly affect NR binding affinity and function. AF1, activation function 1; DBD, DNA-binding domain; LBD, ligand-binding domain; AF2, activation function 2; 9cRA, 9-cis retinoic acid; RXR, retinoid X receptor; CAR, constitutive androstane receptor; FXR, farnesol X receptor; LXR, liver X receptor; PPAR, peroxisomal proliferator and activator receptor; PXR/SXR, pregnane X receptor/steroid and xenobiotic receptor; RAR, retinoic acid receptor.
Journal of Hepatology  , DOI: ( /S (02) )

3. Fig. 2
Schematic representation of the hepatic response to elevated intracellular levels of bile acids. Primary bile acids cholic acid and chenodeoxycholic acid are potent FXR agonists, and directly activate FXR response elements in the BSEP and SHP promoters. SHP interferes with LRH-1 and RXR:RAR transactivation of CYP7A1 and NTCP promoters, respectively, thereby reducing both bile acid synthesis and import. Another important element is the detoxification of lithocholic acid (LCA) by CYP3A4 (CYP3A11 in mice) mediated by PXR/SXR. Whether or not SHP can regulate BSEP promoter activity is unknown and noted by a ‘?’. Note that SHP can autoregulate its own promoter. Taken together, the collective response is to protect the hepatocyte during conditions where the intracellular concentration of bile acids is high, and the composition of the bile acid pool is hepatotoxic. Additional abbreviations noted in the text.
Journal of Hepatology  , DOI: ( /S (02) )

4. Fig. 3
Role of CAR and PXR/SXR in hepatic drug/xenobiotic and bilirubin metabolism. There is substantial evidence that CAR and PXR/SXR regulate the majority of P450 enzymes in the hepatocyte, and this figure briefly depicts a few of the more notable pathways. PXR/SXR is shown as PXR for simplicity. Note that PXR/SXR and CAR both regulate key metabolizing gene families CYP2B and CYP3A, thereby providing functional redundancy for these important metabolic pathways. PXR/SXR can activate the import (OATP2; SLC21A5), metabolism (CYP3A), and export (MDR1 AND MRP2) of drugs and toxins, although a single substance that requires these components for full metabolism has yet to be identified. On the other hand, CAR is emerging as an important regulator of bilirubin metabolism, with evidence of its involvement in all three components, import (OATP4; SLC21A6), conjugation (UGT1A1), and export of conjugated bilirubin (MRP2). CAR is also known to regulate CYP2C and CYP4A family members. Since there is substantial species variability in CAR and PXR/SXR targets, this basic schematic should serve as a conceptual guide and not necessarily definitive. Given the central role of both CAR and PXR/SXR in drug/xenobiotic metabolism, it is clear that any perturbations in these pathways will have ramifications of a host of PXR/SXR and CAR target genes. See text for details.
Journal of Hepatology  , DOI: ( /S (02) )