Interindividual Variability in Gene Expression Profiles in Human Hepatocytes and Comparison with HepaRG Cells

Inter-individual variations in functions other than drug metabolism activity remain poorly elucidated in human liver. In the present study, the whole transcriptomes of several human hepatocyte populations and the differentiated human HepaRG cell line have been analyzed and compared, using oligonucleotide pangenomic microarrays. We show that, while the variation in the percentages of expressed genes did not exceed 14%, huge inter-individual differences in the transcript levels of many genes were observed between the primary human hepatocyte populations. Variable genes were related to various functions; in addition to drug metabolism, they mainly concerned carbohydrate, amino acid and lipid metabolisms. Interestingly, a relationship was evidenced when comparing abnormal basal expression levels of some target genes with their corresponding previously reported fold changes in one out of four human hepatocyte populations treated with the hepatotoxic drug troglitazone and not with other peroxisome proliferator-activated receptor agonists (Rogue et al., 2011). HepaRG cells expressed from 81 to 92% of the active genes in human hepatocytes and in addition, a specific gene subset mainly related to their transformed status, some chromosomal abnormalities and the presence of biliary epithelial cells. Taken altogether, our results support the view that expressing most of the active genes of human hepatocytes the HepaRG cell line is representative of a human hepatocyte population and show that expression of most human hepatic genes can quantitatively greatly vary between individuals, thereby contributing to explain the huge inter-individual variable susceptibility to drugs and other environmental factors