PT  - JOURNAL ARTICLE
AU  - April D Lake
AU  - Petr Novak
AU  - Craig D Fisher
AU  - Jonathan P Jackson
AU  - Rhiannon N. Hardwick
AU  - D. Dean Billheimer
AU  - Walter T Klimecki
AU  - Nathan J Cherrington
TI  - Analysis of Global and ADME Gene Expression In the Progressive Stages of Human Non-Alcoholic Fatty Liver Disease
AID  - 10.1124/dmd.111.040592
DP  - 2011 Jul 07
TA  - Drug Metabolism and Disposition
PG  - dmd.111.040592
4099  - http://dmd.aspetjournals.org/content/early/2011/07/07/dmd.111.040592.short
4100  - http://dmd.aspetjournals.org/content/early/2011/07/07/dmd.111.040592.full
AB  - Non-alcoholic fatty liver disease (NAFLD) is characterized by a series of pathological changes that range from simple fatty liver to non-alcoholic 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. The majority of gene expression changes occurred in the progression from steatosis to NASH. Principal component analysis (PCA) 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 downregulated. These results suggest that uptake transporter genes are coordinately targeted for downregulation 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.