PXR Suppresses PPARα-Dependent HMGCS2 Gene Transcription by Inhibiting the Interaction between PPARα and PGC1α

Abstract

Background: PXR is a xenobiotic-responsive nuclear receptor that controls the expression of drug-metabolizing enzymes. Drug-induced activation of PXR sometimes causes drug–drug interactions due to the induced metabolism of co-administered drugs. Our group recently reported a possible drug–drug interaction mechanism via an interaction between the nuclear receptors CAR and PPARα. As CAR and PXR are structurally and functionally related receptors, we investigated possible crosstalk between PXR and PPARα. Methods: Human hepatocyte-like HepaRG cells were treated with various PXR ligands, and mRNA levels were determined by quantitative reverse transcription PCR. Reporter assays using the HMGCS2 promoter containing a PPARα-binding motif and mammalian two-hybrid assays were performed in HepG2 or COS-1 cells. Results: Treatment with PXR activators reduced the mRNA levels of PPARα target genes in HepaRG cells. In reporter assays, PXR suppressed PPARα-dependent gene expression in HepG2 cells. In COS-1 cells, co-expression of PGC1α, a common coactivator of PPARα and PXR, enhanced PPARα-dependent gene transcription, which was clearly suppressed by PXR. Consistently, in mammalian two-hybrid assays, the interaction between PGC1α and PPARα was attenuated by ligand-activated PXR. Conclusion: The present results suggest that ligand-activated PXR suppresses PPARα-dependent gene expression by inhibiting PGC1α recruitment.

C Allele of the PPARδ+294T>C Polymorphism Confers a Higher Risk of Hypercholesterolemia, but not Obesity and Insulin Resistance: A Systematic Review and Meta-Analysis

“…PPARγ agonists, thiazolidinediones, are widely used in clinics as insulin sensitizers. Being activated by exogenous and endogenous ligands, PPARα and PPARδ exert their functions as transcription factors to activate the transcription of genes involved in lipid metabolic pathways such as lipid transport [86], fatty acid oxidation [87], lipogenesis [88], cholesterol metabolism [89], and ketogenesis [90]. Variations in PPARA or PPARD may lead to aberrant expressions of themselves and their target genes, resulting in obesity, metabolic disorders and cardiovascular disease.…”

The role of pregnane X receptor (PXR) in substance metabolism

“…Carnitine palmitoyltransferase 1A (CPT1A) and mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 (HMGCS2) are two important enzymes which involved in b-oxidation and ketogenesis. In the absence of insulin, the winged helix/forkhead transcription factor FoxA2 activates transcription of CPT1A and HMGCS2 (91). Insulin induces phosphorylation and exonucleation of FoxA2, which activates FoxA2 and suppresses transcription of CPT1A and HMGCS2 (92).…”

The effects of hexabromocyclododecane on the transcriptome and hepatic enzyme activity in three human HepaRG-based models

“…While Canton et al (2008) discussed that PPAR pathway inhibition could be due to the decrease of T4, this mechanism is unlikely to occur with the in vitro models used herein. Alternatively, it has been proposed that the PXR/CAR activation inhibits PPAR-α activation through competition of coactivator peroxisome proliferator-activated receptor g coactivator 1α (Shizu et al, 2021). Since PPAR-α is involved in lipid metabolism, the inhibition of the pathway possibly explains the inhibition of cholesterol metabolism and ethanol effects on histone modifications pathways (Varga et al, 2011).…”