RNA-seq gene expression profiling of RefSeq genes in nuclear RNA from livers of mice treated with the nuclear receptor CAR (Nr1i3) agonist ligand TCPOBOP for 2 week or for 8 week.

PolyA-selected RNA was isolated from the nuclear fraction of frozen liver tissue from adult male and female ICR/CD1 mice that were treated with a TCPOBOP delivered using either a Low Corn Oil vehice or a High Corn Oil vehicle regimen. Livers were collected and nuclear RNA purified and analyzed either 2 week or 8 weeks after initiating TCPOBOP treatment. These samples are part of a study designed to elucidate genes and gene-based mechanisms underlying TCPOBOP-disrupted liver metabolic dysfunction, including the pericentral steatosis seen within 2 weeks of the initial TCPOBOP exposure. Major findings of this work included the following: Early (1-day) TCPOBOP transcriptional responses were enriched for CAR-bound primary response genes, and for lipogenesis and xenobiotic metabolism and oxidative stress protection pathways; late (2-wk) TCPOBOP responses included many CAR binding-independent secondary response genes, with enrichment for macrophage activation, immune response and cytokine and reactive oxygen species production. Late upstream regulators specific to TCPOBOP-exposed male liver were linked to pro-inflammatory responses and hepatocellular carcinoma progression. TCPOBOP administered weekly to male mice using a high corn oil vehicle activated carbohydrate-responsive transcription factor (MLXIPL)-regulated target genes, dysregulated mitochondrial respiratory and translation regulatory pathways, and induced more advanced liver pathology. Overall, TCPOBOP exposure recapitulated histological and gene expression changes characteristic of emerging steatotic liver disease, including secondary gene responses in liver non-parenchymal cells indicative of transition to a more advanced disease state.