Observational Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 28, 2024; 30(4): 332-345
Published online Jan 28, 2024. doi: 10.3748/wjg.v30.i4.332
Circulating microRNA expression and nonalcoholic fatty liver disease in adolescents with severe obesity
Yi-Jie Li, Brittney O Baumert, Nikos Stratakis, Jesse A Goodrich, Hao-Tian Wu, Jing-Xuan He, Yin-Qi Zhao, Max T Aung, Hong-Xu Wang, Sandrah P Eckel, Douglas I Walker, Damaskini Valvi, Michele A La Merrill, Justin R Ryder, Thomas H Inge, Todd Jenkins, Stephanie Sisley, Rohit Kohli, Stavra A Xanthakos, Andrea A Baccarelli, Rob McConnell, David V Conti, Lida Chatzi
Yi-Jie Li, Brittney O Baumert, Jesse A Goodrich, Jing-Xuan He, Yin-Qi Zhao, Max T Aung, Hong-Xu Wang, Sandrah P Eckel, Rob McConnell, David V Conti, Lida Chatzi, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, United States
Nikos Stratakis, Barcelona Institute of Global Health, Barcelona Institute of Global Health, Barcelona 08036, Spain
Hao-Tian Wu, Andrea A Baccarelli, Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032, United States
Douglas I Walker, Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30329, United States
Damaskini Valvi, Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Michele A La Merrill, Department of Environmental Toxicology, University of California, Davis, CA 95616, United States
Justin R Ryder, Thomas H Inge, Department of Surgery, Lurie Children’s Hospital of Chicago, Chicago, IL 60611, United States
Justin R Ryder, Thomas H Inge, Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
Todd Jenkins, Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States
Todd Jenkins, Stavra A Xanthakos, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, United States
Stephanie Sisley, Department of Pediatrics, Children’s Nutrition Research Center USDA/ARS, Baylor College of Medicine, Houston, TX 77030, United States
Rohit Kohli, Department of Gastroenterology, Children’s Hospital Los Angeles, Los Angeles, CA 90027, United States
Stavra A Xanthakos, Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States
Author contributions: Li YJ and Chatzi L designed the research study; Li YJ performed the research; Conti DV, Stratakis N, Goodrich JA, Zhao YQ, Wang HX, and He JX contributed new analytic tools; Ryder JR, Inge TH, Jenkins T, Sisley S, Kohli R and Xanthakos SA contributed data collection; Li YJ wrote the manuscript; Baumert BO, Stratakis N, Goodrich JA, Wu HT, Aung MT, Eckel SP, Walker DI, Valvi D, La Merrill MA, Ryder JR, Inge TH, Jenkins T, Sisley S, Kohli R, Xanthakos SA, Baccarelli AA, McConnell R, Conti DV and Chatzi L reviewed and revised manuscript; all authors have read and approve the final manuscript.
Supported by National Institute of Environmental Health, No. R01ES030691; No. R01ES030364, No. R01ES029944, No. U01HG013288, No. T32-ES013678, No. P30ES007048, No. U2CES030859, No. R01ES032831, No. R01ES033688, No. P30ES023515, and No. P2CES033433; National Human Genome Research Institute and National Institute of Environmental Health, No. U01HG013288; California Environmental Protection Agency, No. 20-E0017; National Cancer Institute and National Institute of Environmental Health, No. P01CA196569; Ministry of Science and Innovation and State Research Agency, No. CEX2018-000806-S; European Union (“NextGenerationEU/PRTR”), No. IJC2020-043630-I; European Union’s Horizon Europe Research And Innovation Programme Under the Marie Skłodowska-Curie Actions Postdoctoral Fellowships, No. 101059245; United States Department of Agriculture, No. 6250-51000-053; National Institutes of Health, No. R01DK128117−01A1; and The Teen-LABS Consortium: National Institute of Diabetes and Digestive and Kidney Diseases, No. UM1DK072493 and No. UM1DK095710.
Institutional review board statement: This study used data from the Teen-LABS study (ClinicalTrials.gov NCT00465829), under a protocol approved by the institutional review boards of the participating institutions: Cincinnati Children’s Hospital Medical Center (Cincinnati, Ohio), Nationwide Children’s Hospital (Columbus, Ohio), University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania), Texas Children’s Hospital (Houston, Texas), and Children’s Hospital of Alabama (Birmingham, Alabama).
Informed consent statement: This is a secondary data analysis, which means we do not have informed consent nor any private information of participants.
Conflict-of-interest statement: There are no conflicts of interest to report.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at chatzi@usc.edu.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Lida Chatzi, MD, PhD, Professor, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, 1845 N. Soto Street, Los Angeles, CA 90032, United States. chatzi@usc.edu
Received: September 29, 2023
Peer-review started: September 29, 2023
First decision: November 6, 2023
Revised: December 4, 2023
Accepted: January 9, 2024
Article in press: January 9, 2024
Published online: January 28, 2024
Abstract
BACKGROUND

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in children and adolescents. NAFLD ranges in severity from isolated hepatic steatosis to nonalcoholic steatohepatitis (NASH), wherein hepatocellular inflammation and/or fibrosis coexist with steatosis. Circulating microRNA (miRNA) levels have been suggested to be altered in NAFLD, but the extent to which miRNA are related to NAFLD features remains unknown. This analysis tested the hypothesis that plasma miRNAs are significantly associated with histological features of NAFLD in adolescents.

AIM

To investigate the relationship between plasma miRNA expression and NAFLD features among adolescents with NAFLD.

METHODS

This study included 81 adolescents diagnosed with NAFLD and 54 adolescents without NAFLD from the Teen-Longitudinal Assessment of Bariatric Surgery study. Intra-operative core liver biopsies were collected from participants and used to characterize histological features of NAFLD. Plasma samples were collected during surgery for miRNA profiling. A total of 843 plasma miRNAs were profiled using the HTG EdgeSeq platform. We examined associations of plasma miRNAs and NAFLD features using logistic regression after adjusting for age, sex, race, and other key covariates. Ingenuity Pathways Analysis was used to identify biological functions of miRNAs that were associated with multiple histological features of NAFLD.

RESULTS

We identified 16 upregulated plasma miRNAs, including miR-193a-5p and miR-193b-5p, and 22 downregulated plasma miRNAs, including miR-1282 and miR-6734-5p, in adolescents with NAFLD. Moreover, 52, 16, 15, and 9 plasma miRNAs were associated with NASH, fibrosis, ballooning degeneration, and lobular inflammation, respectively. Collectively, 16 miRNAs were associated with two or more histological features of NAFLD. Among those miRNAs, miR-411-5p was downregulated in NASH, ballooning, and fibrosis, while miR-122-5p, miR-1343-5p, miR-193a-5p, miR-193b-5p, and miR-7845-5p were consistently and positively associated with all histological features of NAFLD. Pathway analysis revealed that most common pathways of miRNAs associated with multiple NAFLD features have been associated with tumor progression, while we also identified linkages between miR-122-5p and hepatitis C virus and between miR-199b-5p and chronic hepatitis B.

CONCLUSION

Plasma miRNAs were associated with NAFLD features in adolescent with severe obesity. Larger studies with more heterogeneous NAFLD phenotypes are needed to evaluate miRNAs as potential biomarkers of NAFLD.

Keywords: MicroRNA, Nonalcoholic fatty liver disease, Non-alcoholic steatohepatitis, Liver fibrosis, Lobular inflammation, Ballooning degeneration

Core Tip: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, and its prevalence in adolescents is increasing. Studies suggest plasma microRNAs (miRNAs) are dysregulated in NAFLD, but relevant observational studies are scarce. In this study, we analyzed the expression of plasma miRNA in adolescents diagnosed with NAFLD by liver biopsy. We identified associations between histological features of NAFLD and plasma miRNA expression. Further, we found consistent expression of miRNA across different features of NAFLD. Although these results need further testing and validation, our findings suggest these miRNAs could be diagnostic and prognostic biomarkers of NAFLD.