Abstract
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.
Footnotes
This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK068039]; the National Institutes of Health National Institute of Allergy and Infectious Diseases Extramural Activities [Grant AI083927]; the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant HD062489] (to N.J.C.); the National Institutes of Health National Center for Complementary and Alternative Medicine [Grant AT002842] (to C.D.F.); and the National Institutes of Health National Institute of Environmental Health Sciences [Grant ES006694]. The Liver Tissue Cell Distribution System was sponsored by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Contract no. N01-DK-7-0004/HHSN267200700004C].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.040592.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- NAFLD
- nonalcoholic fatty liver disease
- NASH
- nonalcoholic steatohepatitis
- ADME
- absorption, distribution, metabolism, and excretion
- ADR
- adverse drug reaction
- DME
- drug-metabolizing enzyme
- P450
- cytochrome P450
- PCA
- principal component analysis
- RIN
- RNA integrity numbering
- RT-PCR
- reverse transcriptase-polymerase chain reaction
- OATP
- organic anion-transporting polypeptide
- Ct
- cycle thresholds.
- Received May 12, 2011.
- Accepted July 7, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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