Differential Associations of Circulating MicroRNAs With Pathogenic Factors in NAFLD

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous disease driven by genetic and environmental factors. MicroRNAs (miRNAs) serve as pleiotropic post-transcriptional regulators of cellular pathways. Although several miRNAs have been associated with NAFLD and fibrosis, there are limited studies in humans examining their differential association with pathogenic factors or histological features of NAFLD. We examined the differential relationships of five of the best-described circulating microRNAs (miR-34a, miR-122, miR-191, miR-192, and miR-200a) with histological features and pathogenic factors of NAFLD. A cross-sectional study was conducted to examine the relationship between relative levels of circulating microRNAs standardized by z-scores and histological features of NAFLD, common NAFLD genetic polymorphisms, and insulin resistance measured by the enhanced lipoprotein insulin resistance index in 132 subjects with biopsy-proven NAFLD. We found that miR-34a, miR-122, miR-192, miR-200a, but not miR-191, strongly correlate with fibrosis in NAFLD by increases of 0.20 to 0.40 SD (P < 0.005) with each stage of fibrosis. In multivariate analysis, miR-34a, miR-122, and miR-192 levels are independently associated with hepatic steatosis and fibrosis, but not lobular inflammation or ballooning degeneration, whereas miR-200a is only associated with fibrosis. Among the four miRNAs, miR-34a, miR-122, and miR-192 are associated with pathogenic factors of NAFLD, including insulin resistance measured by eLP-IR, patatin-like phospholipase domain containing 3 I148M, and transmembrane 6 superfamily 2 (TM6SF2) E167K polymorphisms. In contrast, miR-200a is only associated with the TM6SF2 E167K variant. Finally, miR-34a has the strongest predictive value for various stages of fibrosis, with C-statistic approximates-combined predictive score for miRNAs. Conclusion: miR-34a, miR-122, miR-192, and miR-200a demonstrate strong associations with NAFLD severity by histology, but differential associations with pathogenic factors. (Hepatology Communications 2020;4:670-680).

Deciphering the role of epigenetic modifications in fatty liver disease: A systematic review

“…MiRNAs are deregulated in NAFLD and have been proposed as useful biomarkers for the diagnosis and stratification of disease severity of NAFLD and NASH 5 . We found 24 studies 2,6‐9,26‐43 that investigated the association of miRNAs with FLD (Table 2). Of these, 13 studies used blood samples, 6,26‐36 three studies used liver tissue 2,37,38 and eight studies used both blood and liver tissue samples 7‐9,39‐43 .…”

“…We found 24 studies 2,6‐9,26‐43 that investigated the association of miRNAs with FLD (Table 2). Of these, 13 studies used blood samples, 6,26‐36 three studies used liver tissue 2,37,38 and eight studies used both blood and liver tissue samples 7‐9,39‐43 . In addition, the studies included population with Asian (n = 9), European (n = 7), North American (n = 6) and South American (n = 2) ancestries with mean age of 46.9 years old.…”

“…MiR-122 is abundant in liver and its function has been extensively studied. 44 Most of the studies (n = 14) included in this review reported that miR-122 was associated with FLD and could be used as biomarker for FLD. Among these, 12 studies 6,7,9,26,[28][29][30][31][32]34,35,40 were measured in blood samples.…”

Impact of maternal obesity and prebiotic supplementation on select maternal milk microRNA levels and correlation with offspring outcomes

“…In addition, Ono et al (57) identified miR-222 as a negative regulator of insulin resistance via the down-regulation of insulin receptor substrate-1 in the liver. An upregulation of miR-200a is associated with non-alcoholic fatty liver disease (58)(59)(60) , and in vitro studies show an increase in miR-200a expression in hepatocytes exposed to NEFA and proinflammatory factors (61) . Similar to miR-222, miR-200a may have been up-regulated in HFS-WM dams due to stress and the positive correlation between female offspring liver TAG and miR-222 and miR-200a may be explained through these inflammatory mechanisms.…”

Exosomal miRNAs as Potential Biomarkers to Monitor Phosphodiesterase 5 Inhibitor Induced Anti-Fibrotic Effects on CCl4 Treated Rats

“…In human NAFLD/NASH studies, increased free-circulating levels of miR-15b, miR-28, miR-122, miR-132, miR-181a, miR-191, miR-192, miR-199a-5p and miR-199a-3p have been observed whereas decreased levels of miR-29c and miR-99a have been reported [ 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 ], which are in line with our findings in the liver of the CCl 4 -treated rats. Our observed inverse correlation of decreased hepatic miR-122 level and increased serum miR-122 level is consistent with previous reports in animal and human studies [ 14 , 31 , 47 , 76 ].…”