Comparative Analysis of Gene Regulation by the Transcription Factor PPAR�� between Mouse and Human

BackgroundStudies in mice have shown that PPAR�� is an important regulator of hepatic lipid metabolism and the acute phase response. However, little information is available on the role of PPAR�� in human liver. Here we set out to compare the function of PPAR�� in mouse and human hepatocytes via analysis of target gene regulation.Methodology/Principal FindingsPrimary hepatocytes from 6 human and 6 mouse donors were treated with PPAR�� agonist Wy14643 and gene expression profiling was performed using Affymetrix GeneChips followed by a systems biology analysis. Baseline PPAR�� expression was similar in human and mouse hepatocytes. Depending on species and time of exposure, Wy14643 significantly induced the expression of 362�C672 genes. Surprisingly minor overlap was observed between the Wy14643-regulated genes from mouse and human, although more substantial overlap was observed at the pathway level. Xenobiotics metabolism and apolipoprotein synthesis were specifically regulated by PPAR�� in human hepatocytes, whereas glycolysis-gluconeogenesis was regulated specifically in mouse hepatocytes. Most of the genes commonly regulated in mouse and human were involved in lipid metabolism and many represented known PPAR�� targets, including CPT1A, HMGCS2, FABP1, ACSL1, and ADFP. Several genes were identified that were specifically induced by PPAR�� in human (MBL2, ALAS1, CYP1A1, TSKU) or mouse (Fbp2, lgals4, Cd36, Ucp2, Pxmp4). Furthermore, several putative novel PPAR�� targets were identified that were commonly regulated in both species, including CREB3L3, KLF10, KLF11 and MAP3K8.Conclusions/SignificanceOur results suggest that PPAR�� activation has a major impact on gene regulation in human hepatocytes. Importantly, the role of PPAR�� as master regulator of hepatic lipid metabolism is generally well-conserved between mouse and human. Overall, however, PPAR�� regulates a mostly divergent set of genes in mouse and human hepatocytes.