title: 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.
authors.affiliation: Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Centre for Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Borlak
authors.affiliation: Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA.
authors.forename: Weida
authors.initials: W
authors.lastname: Tong
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D056487:Chemical and Drug Induced Liver Injury, Chronic / Q000097:blood*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015894:Genome, Human; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects*; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood*; D020411:Oligonucleotide Array Sequence Analysis; D025941:Protein Interaction Mapping; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000378:metabolism
chemical_list: D015415:Biomarkers; D007328:Insulin; D035683:MicroRNAs; D014280:Triglycerides