Mechanistically linked serum miRNAs distinguish between drug induced and fatty liver disease of different grades

Abstract

Hepatic steatosis is characterised by excessive triglyceride accumulation in the form of lipid droplets (LD); however, mechanisms differ in drug induced (DIS) and/or non-alcoholic fatty liver disease (NAFLD). Here we hypothesized distinct molecular circuits of microRNA/LD-associated target genes and searched for mechanistically linked serum and tissue biomarkers that would distinguish between DIS and human NAFLD of different grades. We analysed >800 rat hepatic whole genome data for 17 steatotic drugs and identified 157 distinct miRNAs targeting 77 DIS regulated genes. Subsequently, genomic data of N = 105 cases of human NAFLD and N = 32 healthy controls were compared to serum miRNA profiles of N = 167 NAFLD patients. This revealed N = 195 tissue-specific miRNAs being mechanistically linked to LD-coding genes and 24 and 9 miRNAs were commonly regulated in serum and tissue of advanced and mild NAFLD, respectively. The NASH serum regulated miRNAs informed on hepatic inflammation, adipocytokine and insulin signalling, ER-and caveolae associated activities and altered glycerolipid metabolism. Conversely, serum miRNAs associated with blunt steatosis specifically highlighted activity of FOXO1&HNF4α on CPT2, the lipid droplet and ER-lipid-raft associated PLIN3 and Erlin1. Altogether, serum miRNAs informed on the molecular pathophysiology of NAFLD and permitted differentiation between DIS and NAFLD of different grades.

New microRNA Biomarkers for Drug-Induced Steatosis and Their Potential to Predict the Contribution of Drugs to Non-alcoholic Fatty Liver Disease

“…Another recent study, published while this manuscript was in preparation, searched for mechanistically linked miRNA biomarkers that distinguish between drug-induced steatosis and human NAFLD (Liu et al, 2016). However, only one of the top 10 miRNAs associated with drug-induced steatosis in that study (i.e., miR-21) was also in the list of miRNA biomarkers proposed here.…”

“…The different methodological approaches of both studies could explain this lack of correlation. Liu et al (2016) performed data mining in the open TG-GATEs (a publically available microarray database) and obtained a list of mRNAs, which were differentially expressed in the livers of rats treated with drugs; and then, inferred deregulated miRNAs by using a bioinformatics tool based on human data (miRTar). This approach assume that human and rat miRNA-mRNA interactions are 100% conserved and that all the transcriptomic alterations are mediated by miRNAs.…”

“…This approach assume that human and rat miRNA-mRNA interactions are 100% conserved and that all the transcriptomic alterations are mediated by miRNAs. Secondly, only one of the steatotic drugs selected by Liu et al (2016; i.e., tetracycline) is considered a model steatotic drug, and therefore, the conclusions drawn in both studies are based on two very different sets of compounds.…”

Mechanistic roles of microRNAs in hepatocarcinogenesis: A study of thioacetamide with multiple doses and time-points of rats

“…Being key regulators of multiple biological functions as well as potential promising biomarkers for diseases, miRNAs have been extensively studied for the past decades 31–33 . In this study, we profiled miRNAs from rat livers treated with a TAA at multiple doses over four time points to characterize the dynamic changes of miRNAs expression and explore the mechanistic roles of miRNAs resulting in the carcinogenesis.…”

Potential roles of microRNAs and ROS in colorectal cancer: diagnostic biomarkers and therapeutic targets

“…MicroRNAs concurrently modulate the expression levels of dozens or more messenger RNA (mRNA), and any given mRNA sequence may be targeted by several different microRNAs [9, 10, 12]. To date, microRNAs have been predicted to target and control the expression of at least 30% of all protein-coding genes, and they participate the regulation of nearly every cellular process studied so far [13]. Specifically, microRNAs appear to be involved in multiple pathophysiological networks and in the pathogenesis of a broad-spectrum of human diseases, including cancer and inflammation [14–21].…”