Clinical and Translational Research
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Jul 27, 2022; 14(7): 1382-1397
Published online Jul 27, 2022. doi: 10.4254/wjh.v14.i7.1382
Transcriptome changes in stages of non-alcoholic fatty liver disease
Jihad Aljabban, Michael Rohr, Saad Syed, Kamal Khorfan, Vincent Borkowski, Hisham Aljabban, Michael Segal, Mohamed Mukhtar, Mohammed Mohammed, Maryam Panahiazar, Dexter Hadley, Ryan Spengler, Erin Spengler
Jihad Aljabban, Vincent Borkowski, Michael Segal, Ryan Spengler, Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
Michael Rohr, Department of Medicine, University of Central Florida College of Medicine, Orlando, FL 32827, United States
Saad Syed, Department of Medicine, Northwestern Memorial Hospital, Chicago, IL 60611, United States
Kamal Khorfan, Department of Gastroenterology and Hepatology, University of California San Francisco-Fresno , Fresno, CA 93701, United States
Hisham Aljabban, Department of Medicine, Barry University, Miami, FL 33161, United States
Mohamed Mukhtar, Department of Medicine, Michigan State University College of Human Medicine, East Lansing, MI 49503, United States
Mohammed Mohammed, Department of Medicine, Windsor University School of Medicine, Saint Kitts 1621, Cayon, Saint Kitts and Nevis
Maryam Panahiazar, Department of Surgery, University of California San Francisco, San Francisco, CA 94305, United States
Dexter Hadley, Department of Artificial Intelligence, Pathology, University of Central Florida College of Medicine , Orlando, FL 32827, United States
Erin Spengler, Department of Gastroenterology and Hepatology, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
Author contributions: All authors contributed to conception or designing of the work, data collection, drafting manuscript, critical revision of manuscript, final edits and approval the manuscript.
Institutional review board statement: Data was publicly available so IRB approval was not needed.
Conflict-of-interest statement: None of the authors have any conflict of interest.
Data sharing statement: Data was taken by already available public pathologic samples.
CONSORT 2010 statement: The authors have read the CONSORT 2010 statement, and the manuscript was prepared and revised according to the CONSORT 2010 statement.
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: Jihad Aljabban, MD, MSc, Academic Research, Doctor, Department of Medicine, University of Wisconsin Hospital and Clinics, 600 Highland Avenue, Madison, WI 53792, United States. jaljabban@uwhealth.org
Received: March 2, 2022
Peer-review started: March 2, 2022
First decision: April 13, 2022
Revised: April 29, 2022
Accepted: June 14, 2022
Article in press: June 14, 2022
Published online: July 27, 2022
Processing time: 147 Days and 12.8 Hours
Abstract
BACKGROUND

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States and globally. The currently understood model of pathogenesis consists of a ‘multiple hit’ hypothesis in which environmental and genetic factors contribute to hepatic inflammation and injury.

AIM

To examine the genetic expression of NAFLD and non-alcoholic steatohepatitis (NASH) tissue samples to identify common pathways that contribute to NAFLD and NASH pathogenesis.

METHODS

We employed the Search Tag Analyze Resource for Gene Expression Omnibus platform to search the The National Center for Biotechnology Information Gene Expression Omnibus to elucidate NAFLD and NASH pathology. For NAFLD, we conducted meta-analysis of data from 58 NAFLD liver biopsies and 60 healthy liver biopsies; for NASH, we analyzed 187 NASH liver biopsies and 154 healthy liver biopsies.

RESULTS

Our results from the NAFLD analysis reinforce the role of altered metabolism, inflammation, and cell survival in pathogenesis and support recently described contributors to disease activity, such as altered androgen and long non-coding RNA activity. The top upstream regulator was found to be sterol regulatory element binding transcription factor 1 (SREBF1), a transcription factor involved in lipid homeostasis. Downstream of SREBF1, we observed upregulation in CXCL10, HMGCR, HMGCS1, fatty acid binding protein 5, paternally expressed imprinted gene 10, and downregulation of sex hormone-binding globulin and insulin-like growth factor 1. These molecular changes reflect low-grade inflammation secondary to accumulation of fatty acids in the liver. Our results from the NASH analysis emphasized the role of cholesterol in pathogenesis. Top canonical pathways, disease networks, and disease functions were related to cholesterol synthesis, lipid metabolism, adipogenesis, and metabolic disease. Top upstream regulators included pro-inflammatory cytokines tumor necrosis factor and IL1B, PDGF BB, and beta-estradiol. Inhibition of beta-estradiol was shown to be related to derangement of several cellular downstream processes including metabolism, extracellular matrix deposition, and tumor suppression. Lastly, we found riciribine (an AKT inhibitor) and ZSTK-474 (a PI3K inhibitor) as potential drugs that targeted the differential gene expression in our dataset.

CONCLUSION

In this study we describe several molecular processes that may correlate with NAFLD disease and progression. We also identified ricirbine and ZSTK-474 as potential therapy.

Keywords: Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Bioinformatics; AKT inhibitor; Therapy

Core Tip: Our results from the non-alcoholic fatty liver disease analysis reinforce the role of altered metabolism, inflammation, and cell survival in pathogenesis and support recently described contributors to disease activity, such as altered androgen and lncrna activity. The top upstream regulator was found to be sterol regulatory element binding transcription factor 1 (SREBF1), a transcription factor involved in lipid homeostasis. Downstream of SREBF1, we observed upregulation in CXCL10, HMGCR, HMGCS1, FABP5, PEG10, and downregulation of SHBG and IGF1. These molecular changes reflect low-grade inflammation secondary to accumulation of fatty acids in the liver. Our results from the NASH analysis emphasized the role of cholesterol in pathogenesis. Top upstream regulators included pro-inflammatory cytokines TNF and IL1B, PDGF BB, and beta-estradiol. Inhibition of beta-estradiol was shown to be related to derangement of several cellular downstream processes including metabolism, extracellular matrix deposition, and tumor suppression. Lastly, we found riciribine (an AKT inhibitor) and ZSTK-474 (a PI3K inhibitor) as potential drugs that targeted the differential gene expression in our dataset.