Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression: Diagnostic and mechanistic relevanceBiosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA, USA.
Oxford Liver Unit, NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
Division of Diagnostics and Specialist Medicine, Department of Health, Medicine, and Caring Sciences, Linköping University, Linköping, Sweden.
NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.
Institute of Cardiometabolism and Nutrition, Pitié Salpêtrière Hospital, Paris, France; Assistance Publique - Hopitaux de Paris, Paris, France.
Metabolic Liver Research Program, I. Department of Medicine, University Medical Center of Johannes Gutenberg-University Mainz, Mainz, Germany.
Hepatology Department, Angers University Hospital, Angers, France.
Institute of Cardiometabolism and Nutrition, Pitié Salpêtrière Hospital, Paris, France; Assistance Publique - Hopitaux de Paris, Paris, France.
Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy.
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK.
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
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2022 (English)In: JHEP Reports, E-ISSN 2589-5559, Vol. 4, no 2, article id 100409Article in journal (Refereed) Published
Abstract [en]
Background & Aims: Serum microRNA (miRNA) levels are known to change in non-alcoholic fatty liver disease (NAFLD) and may serve as useful biomarkers. This study aimed to profile miRNAs comprehensively at all NAFLD stages.
Methods: We profiled 2,083 serum miRNAs in a discovery cohort (183 cases with NAFLD representing the complete NAFLD spectrum and 10 population controls). miRNA libraries generated by HTG EdgeSeq were sequenced by Illumina NextSeq. Selected serum miRNAs were profiled in 372 additional cases with NAFLD and 15 population controls by quantitative reverse transcriptase PCR.
Results: Levels of 275 miRNAs differed between cases and population controls. Fewer differences were seen within individual NAFLD stages, but miR-193a-5p consistently showed increased levels in all comparisons. Relative to NAFL/non-alcoholic steatohepatitis (NASH) with mild fibrosis (stage 0/1), 3 miRNAs (miR-193a-5p, miR-378d, and miR378d) were increased in cases with NASH and clinically significant fibrosis (stages 2-4), 7 (miR193a-5p, miR-378d, miR-378e, miR-320b, miR-320c, miR-320d, and miR-320e) increased in cases with NAFLD activity score (NAS) 5-8 compared with lower NAS, and 3 (miR-193a-5p, miR-378d, and miR-378e) increased but 1 (miR-19b-3p) decreased in steatosis, activity, and fibrosis (SAF) activity score 2-4 compared with lower SAF activity. The significant findings for miR-193a-5p were replicated in the additional cohort with NAFLD. Studies in Hep G2 cells showed that following palmitic acid treatment, miR-193a-5p expression decreased significantly. Gene targets for miR-193a-5p were investigated in liver RNAseq data for a case subgroup (n = 80); liver GPX8 levels correlated positively with serum miR-193a-5p.
Conclusions: Serum miR-193a-5p levels correlate strongly with NAFLD activity grade and fibrosis stage. MiR-193a-5p may have a role in the hepatic response to oxidative stress and is a potential clinically tractable circulating biomarker for progressive NAFLD.
Lay summary: MicroRNAs (miRNAs) are small pieces of nucleic acid that may turn expression of genes on or off. These molecules can be detected in the blood circulation, and their levels in blood may change in liver disease including non-alcoholic fatty liver disease (NAFLD). To see if we could detect specific miRNA associated with advanced stages of NAFLD, we carried out miRNA sequencing in a group of 183 patients with NAFLD of varying severity together with 10 population controls. We found that a number of miRNAs showed changes, mainly increases, in serum levels but that 1 particular miRNA miR-193a-5p consistently increased. We confirmed this increase in a second group of cases with NAFLD. Measuring this miRNA in a blood sample may be a useful way to determine whether a patient has advanced NAFLD without an invasive liver biopsy.
Place, publisher, year, edition, pages
Elsevier, 2022. Vol. 4, no 2, article id 100409
Keywords [en]
ALT, alanine aminotransferase, AST, aspartate aminotransferase, AUROC, area under the receiver operating characteristic, Biomarker, CPM, counts per million, Ct, cycle threshold, ER, endoplasmic reticulum, FC, fold change, FIB-4, fibrosis-4, FLIP, fatty liver inhibition of progression, GTEx, Genotype-Tissue Expression, MicroRNA, NAFL, non-alcoholic fatty liver, NAFLD, non-alcoholic fatty liver disease, NAS, NAFLD activity score, NASH, non-alcoholic steatohepatitis, Non-alcoholic fatty liver disease, PCA, principal component analysis, SAF, steatosis–activity–fibrosis, Sequencing, TGF-β, transforming growth factor-beta, cDNA, complementary DNA, logFC, log2 fold change, miRNA, microRNA, qPCR, quantitative PCR
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:oru:diva-96669DOI: 10.1016/j.jhepr.2021.100409ISI: 000748575500001PubMedID: 35072021Scopus ID: 2-s2.0-85122616328OAI: oai:DiVA.org:oru-96669DiVA, id: diva2:1631764
2022-01-252022-01-252024-06-24Bibliographically approved