To determine whether PPARα response was hepatocyte-autonomous, we challenged wild-type (WT), floxed Pparαhep+/+, Pparα−/− and Pparαhep−/− mice with the PPARα agonist fenofibrate. We measured mRNA expressions of PPARα target genes, including Cyp4a10 (figure 2A) and Cyp4a14 (figure 2B). Their expressions were strongly induced by fenofibrate in WT and in floxed Pparαhep+/+ mice compared with Pparα−/− and Pparαhep−/− mice. These samples were also used for pangenomic expression profiling through microarray analysis (figure 2C). Differentially expressed gene (DEG) analysis was subjected to hierarchical clustering, highlighting similar expression profiles between WT and floxed Pparαhep+/+ mice within fenofibrate-treated or vehicle-treated groups. Whole-body Pparα−/− and Pparαhep−/− mice were unresponsive to fenofibrate, suggesting that fenofibrate-induced hepatic changes were mainly due to autonomous hepatocyte responses, not secondary to extrahepatic PPARα activation. GO biological function analysis revealed that fenofibrate upregulated lipid metabolism, and repressed immune and defence response, metabolic responses, and glycosylation and glycoprotein metabolism (figure 2C, groups 1, 2, 6 and 7). However, untreated Pparα−/− and Pparαhep−/− mice showed marked differences (figure 2C, groups 3, 4, 8 and 9). This implies that the absence of extrahepatic PPARα
