Analysis of Global and Absorption, Distribution, Metabolism, and Elimination Gene Expression in the Progressive Stages of Human Nonalcoholic Fatty Liver Disease
Open accessAbstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by a series of pathological changes that range from simple fatty liver to nonalcoholic steatohepatitis (NASH). The objective of this study is to describe changes in global gene expression associated with the progression of human NAFLD. This study is focused on the expression levels of genes responsible for the absorption, distribution, metabolism, and elimination (ADME) of drugs. Differential gene expression between three clinically defined pathological groups-normal, steatosis, and NASH-was analyzed. Genome-wide mRNA levels in samples of human liver tissue were assayed with Affymetrix GeneChip Human 1.0ST arrays. A total of 11,633 genes exhibited altered expression out of 33,252 genes at a 5% false discovery rate. Most gene expression changes occurred in the progression from steatosis to NASH. Principal component analysis revealed that hepatic disease status was the major determinant of differential ADME gene expression rather than age or sex of sample donors. Among the 515 drug transporters and 258 drug-metabolizing enzymes (DMEs) examined, uptake transporters but not efflux transporters or DMEs were significantly over-represented in the number of genes down-regulated. These results suggest that uptake transporter genes are coordinately targeted for down-regulation at the global level during the pathological development of NASH and that these patients may have decreased drug uptake capacity. This coordinated regulation of uptake transporter genes is indicative of a hepatoprotective mechanism acting to prevent accumulation of toxic intermediates in disease-compromised hepatocytes.
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Bulk RNA-seq liver gene signatures from whole liver, isolated hepatocytes, non-parenchymal cells, or plasma correlate with disease features and sometimes predict transition from MASLD to MASH.
“Through the use of bulk RNA-seq, liver gene signatures were derived from whole liver, isolated hepatocytes, isolated non-parenchymal cells, or plasma that correlated with various disease features and, in some cases, predicted the transition from MASLD to MASH (44, 116-122).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [120]
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- Authors
- Lake, A. D., Novak, P., Fisher, C. D., Jackson, J. P., Hardwick, R. N., Billheimer, D. D., Klimecki, W. T., & Cherrington, N. J.
- Affiliations
- University of Arizona (US)
- ORCID
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2011-10
- Volume
- 39
- Issue
- 10
- Pages
- 1954-1960
- ISSN
- 0090-9556 (ISSN-L)
- PMC
- PMC3186211
- OpenAlex
- W1994834284
- Cited by
- 167
- References
- 41
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 6 · 2023: 9 · 2022: 7 · 2021: 12 · 2020: 14 · 2019: 14 · 2018: 15 · 2017: 23 · 2016: 12 · 2015: 15 · 2014: 17 · 2013: 7 · 2012: 5
- FWCI
- 9.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ASEP (publishedVersion)
- Funders
- University of Arizona Cancer Center
- University of Arizona
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (AI-083927, R01AI083927)
- National Institute of Diabetes and Digestive and Kidney Diseases (N01-DK-7-0004/ HHSN267200700004C, R01DK068039, DK-068039)
- National Institute of Environmental Health Sciences (ES-006694, T32ES007091, P30ES006694)
- U.S. National Library of Medicine (HHSN267200700004C, HHSN267200700004G)
- National Center for Complementary and Integrative Health (AT002842, F31AT002842)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-062489, R01HD062489)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, hepatic steatosis, drug transporters, drug-metabolizing enzymes, uptake transporters, efflux pumps, hepatoprotection, disease progression, hepatic gene expression
- MeSH terms
- Absorption, Biological Transport, Pharmaceutical Preparations, Fatty Liver, Humans, Liver, RNA, Messenger, Tissue Distribution, Down-Regulation, Gene Expression, Disease Progression, Microarray Analysis, Genome-Wide Association Study, Non-alcoholic Fatty Liver Disease
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