Generic Portal

TY - JOUR

T1 - Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression

T2 - Diagnostic and mechanistic relevance

AU - Johnson, Katherine

AU - Leary, Peter J.

AU - Govaere, Olivier

AU - Barter, Matthew J.

AU - Charlton, Sarah H.

AU - Cockell, Simon J.

AU - Tiniakos, Dina

AU - Zatorska, Michalina

AU - Bedossa, Pierre

AU - Brosnan, M. Julia

AU - Cobbold, Jeremy F.

AU - Ekstedt, Mattias

AU - Aithal, Guruprasad P.

AU - Clément, Karine

AU - Schattenberg, J. rn M.

AU - Boursier, Jerome

AU - Ratziu, Vlad

AU - Bugianesi, Elisabetta

AU - Anstee, Quentin M.

AU - Daly, Ann K.

AU - LITMUS Consortium Investigators§

AU - Clark, James

AU - Cordell, Heather J.

AU - Darlay, Rebecca

AU - Day, Christopher P.

AU - Hardy, Tim

AU - Liu, Yang-Lin

AU - Oakley, Fiona

AU - Palmer, Jeremy

AU - Queen, Rachel

AU - Wonders, Kristy

AU - Bossuyt, Patrick M.

AU - Holleboom, Adriaan G.

AU - Zafarmand, Hadi

AU - Vali, Yasaman

AU - Lee, Jenny

AU - Clement, Karine

AU - Pais, Raluca

AU - Schuppan, Detlef

AU - Allison, Michael

AU - Cuenca, Sergio Rodriguez

AU - Pellegrinelli, Vanessa

AU - Vacca, Michele

AU - Vidal-Puig, Antonio

AU - Hyötyläinen, Tuulia

AU - McGlinchey, Aidan

AU - Orešič, Matej

AU - Sen, Partho

AU - Mato, Jose

AU - Millet, Óscar

AU - Dufour, Jean-Francois

AU - Harrison, Stephen

AU - Neubauer, Stefan

AU - Pavlides, Michael

AU - Mozes, Ferenc

AU - Akhtar, Salma

AU - Banerjee, Rajarshi

AU - Kelly, Matt

AU - Shumbayawonda, Elizabeth

AU - Dennis, Andrea

AU - Erpicum, Charlotte

AU - Romero-Gomez, Manuel

AU - Gallego-Durán, Rocío

AU - Fernández, Isabel

AU - Karsdal, Morten

AU - Leeming, Diana

AU - Fisker, Mette Juul

AU - Erhardtsen, Elisabeth

AU - Rasmussen, Daniel

AU - Qvist, Per

AU - Sinisi, Antonia

AU - Sandt, Estelle

AU - Tonini, Maria Manuela

AU - Parola, Maurizio

AU - Rosso, Chiara

AU - Marra, Fabio

AU - Gastaldelli, Amalia

AU - Francque, Sven

AU - Kechagias, Stergios

AU - Yki-Järvinen, Hannele

AU - Porthan, Kimmo

AU - van Mil, Saskia

AU - Papatheodoridis, George

AU - Cortez-Pinto, Helena

AU - Valenti, Luca

AU - Petta, Salvatore

AU - Miele, Luca

AU - Geier, Andreas

AU - Trautwein, Christian

AU - Hockings, Paul

AU - Newsome, Phil

AU - Wenn, David

AU - Pereira Rodrigues, Cecília Maria

AU - Hanf, R. my

AU - Chaumat, Pierre

AU - Rosenquist, Christian

AU - Trylesinski, Aldo

AU - Ortiz, Pablo

AU - Duffin, Kevin

AU - Yunis, Carla

AU - Miller, Melissa

AU - Tuthill, Theresa

AU - Ertle, Judith

AU - Younes, Ramy

AU - Alexander, Leigh

AU - Ostroff, Rachel

AU - Kjær, Mette Skalshøi

AU - Mikkelsen, Lars Friis

AU - Brass, Clifford

AU - Jennings, Lori

AU - Balp, Maria-Magdalena

AU - Martic, Miljen

AU - Hanauer, Guido

AU - Shankar, Sudha

AU - Torstenson, Richard

AU - Fournier, C. line

AU - Ehman, Richard

AU - Kalutkiewicz, Michael

AU - Pepin, Kay

AU - Myers, Joel

AU - Shevell, Diane

AU - Ho, Gideon

AU - Landgren, Henrik

AU - Myers, Rob

AU - Doward, Lynda

AU - Whalley, Diane

AU - Twiss, James

N1 - Funding Information: This study has been performed as part of the LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis) project, which has received funding from the Innovative Medicines Initiative (IMI2) Program of the European Union under Grant Agreement 777377; this Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. The current study was also supported by the Newcastle NIHR Biomedical Research Centre and the European NAFLD Registry. Publisher Copyright: © 2021 The Author(s)

PY - 2022/2/1

Y1 - 2022/2/1

N2 - 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.

AB - 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.

KW - Biomarker

KW - MicroRNA

KW - Non-alcoholic fatty liver disease

KW - Sequencing

UR - http://www.scopus.com/inward/record.url?scp=85122616328&partnerID=8YFLogxK

U2 - 10.1016/j.jhepr.2021.100409

DO - 10.1016/j.jhepr.2021.100409

M3 - Article

C2 - 35072021

VL - 4

JO - JHEP Reports

JF - JHEP Reports

SN - 2589-5559

IS - 2

M1 - 100409

ER -