Expression Variability of Absorption, Distribution, Metabolism, Excretion–Related MicroRNAs in Human Liver: Influence of Nongenetic Factors and Association with Gene Expression

Abstract

Genes that are important for the detoxification of drugs and other xenobiotics show a high degree of interindividual variation attributable to regulation by diverse genetic, nongenetic, and epigenetic mechanisms including microRNAs (miRNAs). We selected a set of 56 miRNAs predicted to target the 39-untranslated region of absorption, distribution, metabolism, excretion (ADME) genes to assess their hepatic expression levels and interindividual variability in a well-documented human liver tissue cohort (n = 92), together with the well-known hepatic miRNAs miR-122, miR-21, miR-27b, and miR-148a. Quantification by stem-loop real-time reversetranscription polymerase chain reaction confirmed high expression for these microRNAs and revealed particularly strong variability of expression (>1000-fold) for miR-539, miR-200c, miR-31, miR-15a, and miR-22. Association analysis revealed a high degree of correlation among various miRNAs, suggesting coregulation. Statistical analysis considering liver donor meta-data including correction for multiple testing revealed strongly elevated levels of miR-21, miR-34a, miR-130b, and miR-132 in cholestatic liver and of miR-21 and miR-130b during inflammation, as indicated by elevated C-reactive protein levels in serum. Although none of the miRNAs was strongly associated with sex, several miRNAs, including miR-34a and miR-200a/b, were positively correlated with age. Association analysis with ADME gene expression profiles and with cytochrome P450 gene expression phenotypes (mRNA, protein, enzymatic activity) revealed numerous significant correlations. Negatively affected protein and/or activity levels were observed for CYP1A1 (e.g., miR-132, miR-142-3p, miR-21), CYP2A6 (miR-142-3p, miR-21), CYP2C19 (e.g., miR-130b, miR-185, miR-34a), and CYP2E1 (miR-10a, let-7g, miR-200c). These data should be useful to further elucidate regulatory functions of miRNAs in liver pathophysiology and regulation of ADME gene expression.

Polymorphism in miR-31 and miR-584 binding site in the angiotensinogen gene differentially influences body fat distribution in both sexes

“…In subjects with the C allele, AGT expression is decreased, which may eventually result in lower AGT levels. Similarly to AGT, miR-31 was shown to be expressed both in adipose tissue (Tang et al 2009) and in the liver, where the expression of miR-31 is higher in men than in women (Rieger et al 2013). The ''physical contact'' between miR-31 and angiotensinogen may thus occur both …”

“…The sex differences were also replicated in human fatty tissue (Park et al 2013) and may be linked to sex hormone regulation of AGT expression, which has been confirmed in laboratory rodents (Stavréus-Evers et al 2001;Ding et al 2001). The results of our study suggest that similar effects can be present in humans in the case of the ?11525 C/A (rs7079) polymorphism in miR-31 and miR-584 binding site of the angiotensinogen gene; sex-related differences in miRNA expression observed in the case of miR-31 (Rieger et al 2013) can be a contributing factor. Our study has several limitations.…”

MicroRNA hsa-miR-29a-3p modulates CYP2C19 in human liver cells

“…Evidence documented that miRNAs play an important role in the modulation of the production of drug metabolizing enzymes and transporters through multi-directional interactions among environmental stimuli, the expression of miRNA molecules and genetic polymorphisms [26][27][28][29][30][31][32][33]. As miRNA expression has been reported to be affected by drugs and since miRNAs themselves may affect drug metabolism and toxicity, miRNA expression possesses a significant potential for affecting drug efficacy and drug safety.…”

Function and clinical potential of microRNAs in hepatocellular carcinoma

“…Several miRNAs are associated with glucose metabolism, including miR122, miR34a, miR103/107, let-7 and miR143 (38). It has also been reported that miR122 and miR27b are associated with lipid metabolism, miR122, miR485-3p and let-7 are involved in iron metabolism, while miR132/142-3p/21, miR142-3p/21 and miR130b/185/34a are involved in the metabolism of drugs and xenobiotic substances (39). In conclusion, miRNAs play pivotal roles in regulating multiple aspects of liver physiology.…”