Transcriptomic signatures of peroxisome proliferator-activated receptor a (PPARa) in different mouse liver models identify novel aspects of its biology

Szalowska, E.; Tesfay, H.A.; Hijum, S.A.F.T. van; Kersten, A.H.


Background The peroxisome proliferator-activated receptor alpha (PPARa) is a ligand-activated transcription factor that regulates lipid catabolism and inflammation and is hepatocarcinogenic in rodents. It is presumed that the functions of PPARa in liver depend on cross-talk between parenchymal (hepatocytes) and non-parenchymal (Kupffer and endothelial cells) fractions as well as inter-organ interactions. In order to determine how cellular composition and inter-organ interactions influence gene expression upon pharmacological activation of PPARa, we performed a meta-analysis of transcriptomics data obtained from mouse hepatocytes (containing only the parenchymal fraction), mouse liver slices (containing both fractions), and mouse livers exposed to a PPARa agonist. The aim was to obtain a comprehensive view of common and model-specific PPARa-dependent genes and biological processes to understand the impact of cross-talk between parenchymal and non-parenchymal fractions as well as the effect of inter-organ interactions on the hepatic PPARa transcriptome. To this end we analyzed microarray data of experiments performed in mouse primary hepatocytes treated with the PPARa agonist Wy14643 for 6 or 24 h (in vitro), mouse precision cut liver slices treated with Wy14643 for 24 h (ex vivo), and livers of wild type and Ppara knockout mice treated with Wy14643 for 6 h or 5 days (in vivo). Results In all models, activation of PPARa significantly altered processes related to various aspects of lipid metabolism. In ex vivo and in vivo models, PPARa activation significantly regulated processes involved in inflammation; these processes were unaffected in hepatocytes. Only in vivo models showed significant regulation of genes involved in coagulation, carcinogenesis, as well as vesicular trafficking and extracellular matrix. Conclusions PPARa-dependent regulation of genes/processes involved in lipid metabolism is mostly independent of the presence of non-parenchymal cells or systemic factors, as it was observed in all liver models. PPARa-dependent regulation of inflammatory genes requires the presence of non-parenchymal cells, as it was observed only ex vivo and in vivo. However, the full spectrum of PPARa biology at the level of lipid metabolism, immunity, carcinogenesis, as well as novel aspects of PPARa signaling such as coagulation, vesicular trafficking and the extracellular matrix, seems to require systemic factors, as it was observed exclusively in vivo.