Long noncoding RNA LINC00844‐mediated molecular network regulates expression of drug metabolizing enzymes and nuclear receptors in HepaRG cells

Abstract

Noncoding RNAs, such as long noncoding RNAs (lncRNAs) and microRNAs (miRNAs), regulate gene expression in many physiological and pathological processes, including drug metabolism. Drug metabolizing enzymes (DMES) are critical components in drug‐induced liver toxicity. In this study, we used human hepatic HepaRG cells treated with 5 or 10 mM acetaminophen (APAP) as our model system and identified LINC00844 as a toxicity‐associated lncRNA. We analyzed the expression profiles and the correlations between the expression of long noncoding RNAs and key enzymes for acetaminophen metabolism in humans. Our results showed that lncRNA LINC00844 is enriched in the liver and its expression correlates positively with that of CYP3A4, CYP2E1, SULT2A1, NR1I2, and HNF4A mRNA transcripts. We demonstrated that LINC00844 regulates the expression of these five genes in HepaRG cells using gain‐ and loss‐of‐function assays. Further, we discovered that LINC00844 was predominantly localized in the cytoplasm and acted as a hsa‐miR‐486‐5p sponge, via direct binding, to protect SULT2A1 from miRNA‐mediated gene silencing. Our data also showed that hsa‐miR‐486‐5p upregulated the expression of CYP3A4, SULT2A1, NR1I2, and HNF4A by positively regulating LINC00844. We depict a LINC00844‐mediated regulatory network that involves miRNA and NRs and influences the expression of DMEs.Support or Funding InformationFDA E0753201