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Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression: Diagnostic and mechanistic relevance

Lookup NU author(s): Dr Katherine JohnsonORCiD, Dr Peter Leary, Dr Olivier GovaereORCiD, Dr Matthew Barter, Sarah Charlton, Dr Simon CockellORCiD, Dr Dina Tiniakos, Michalina Zatorska, Professor Pierre Bedossa, Professor Quentin AnsteeORCiD, Professor Ann DalyORCiD



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


© 2021 The Author(s)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.

Publication metadata

Author(s): Johnson K, Leary PJ, Govaere O, Barter MJ, Charlton SH, Cockell SJ, Tiniakos D, Zatorska M, Bedossa P, Brosnan MJ, Cobbold JF, Ekstedt M, Aithal GP, Clement K, Schattenberg JM, Boursier J, Ratziu V, Bugianesi E, Anstee QM, Daly AK, LITMUS Consortium Investigators

Publication type: Article

Publication status: Published

Journal: JHEP Reports

Year: 2022

Volume: 4

Issue: 2

Print publication date: 01/02/2022

Online publication date: 25/11/2021

Acceptance date: 09/11/2021

Date deposited: 26/01/2022

ISSN (electronic): 2589-5559

Publisher: Elsevier B.V.


DOI: 10.1016/j.jhepr.2021.100409


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Funder referenceFunder name
... the European Union under Grant Agreement 777377
also supported by the Newcastle NIHR Biomedical Research Centre and the European NAFLD Registry.
part of the LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis) project, which has received funding from the Innovative Medicines Initiative (IMI2) Program of ...
this Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.