The Nuclear Receptor PXR in Chronic Liver Disease

Abstract

Pregnane X receptor (PXR), a nuclear receptor known for modulating the transcription of drug metabolizing enzymes and transporters (DMETs), such as cytochrome P450 3A4 and P-glycoprotein, is functionally involved in chronic liver diseases of different etiologies. Furthermore, PXR activity relates to that of other NRs, such as constitutive androstane receptor (CAR), through a crosstalk that in turn orchestrates a complex network of responses. Thus, besides regulating DMETs, PXR signaling is involved in both liver damage progression and repair and in the neoplastic transition to hepatocellular carcinoma. We here summarize the present knowledge about PXR expression and function in chronic liver diseases characterized by different etiologies and clinical outcome, focusing on the molecular pathways involved in PXR activity. Although many molecular details of these finely tuned networks still need to be fully understood, we conclude that PXR and its modulation could represent a promising pharmacological target for the identification of novel therapeutical approaches to chronic liver diseases.

A Quantitative Systems Pharmacology Platform Reveals NAFLD Pathophysiological States and Targeting Strategies

“…These transporters mediate the hepatic disposition of drugs, xenobiotic metabolites, and endogenous intermediates and metabolites. Targeting NAFLD-associated hepatic proteins that have critical roles both in xenobiotic and endobiotic metabolism may be an emerging theme (see Discussion and [52]) that can be extended to nuclear receptor transcription factors as the diverse drugs tetracycline, SN-38, and the endogenous steroid, pregnanolone, have been shown to interact with PXR [53,54]. In a parallel CMap analysis based on queries derived from 12 patient subtype signatures (complementary to the set of 12 signatures derived from the unsupervised clusters, Table S4; Data files S3-S5), 17/25 of the same predicted drugs (Table 1) were also identified and enriched in the highest ranked drugs.…”

Differentiating between liver diseases by applying multiclass machine learning approaches to transcriptomics of liver tissue or blood-based samples

“…AKR1B10 has been reported as an effective biomarker of advanced liver fibrosis and liver cancer (36,37). The pregnane X receptor (PXR) activation pathway was also highly enriched across many pairwise comparisons and has been implicated in chronic liver disease (38). The pairwise comparisons involving AH and AC conditions were enriched for ethanol degradation pathways (39) by differential expression of J o u r n a l P r e -p r o o f CYP2A7 in our gene signature.…”

“… 36 , 37 The pregnane X receptor activation pathway was also highly enriched across many pairwise comparisons and has been implicated in chronic liver disease. 38 The pairwise comparisons involving AH and AC conditions were enriched for ethanol degradation pathways 39 by differential expression of CYP2A7 in our gene signature. Changes in expression of CYP2A genes in liver tissue have been linked with NAFLD and alcohol-associated liver disease.…”

Transcriptional Regulation of Hepatic Autophagy by Nuclear Receptors

“…They are either ligand-dependent or -independent transcription factors that play key roles in almost every mammalian physiology. Dysfunctions of nuclear receptor (NR) signaling pathways often become culprits that lead to many human diseases including liver diseases [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. For a long time, autophagy regulation has been considered to exclusively occur in cytoplasm.…”