We next used Pparαhep−/− mice to determine the contribution of hepatocyte PPARα, and compared it with Pparα−/− and WT mice. We measured FFA and β-hydroxybutyrate (ketonaemia) levels in fasted and non-fasted mice (figure 4A). Plasma FFA was elevated in fasting mice of all three genotypes, but was significantly higher in Pparαhep−/− and Pparα−/− mice compared with controls. Fasting strongly increased ketone body levels in WT mice and to a lesser degree in Pparαhep−/− and Pparα−/− mice. This suggests that hepatic PPARα is required for FFA disposal and for β-hydroxybutyrate production. Correspondingly, fasting Pparαhep−/− and Pparα−/− mice showed elevated hepatic triglycerides and cholesterol esters (figure 4B), and substantial centrilobular steatosis (figure 4C), confirming that hepatic PPARα expression is required for fasting-induced FFA catabolism. PPARα absence led to defective expressions of PPARα target genes (figure 4D), including those involved in fatty acid catabolism and processing in lipid droplets (figure 4E). As a consequence of PPARα deficiency in hepatocytes, Pparαhep−/− mice exhibit a distinct fasting-induced fatty acid profile with a significant increase in oleic acid (C18:1n–9) and linoleic acid (C18:2n–6) when compared with WT mice (see online supplementary file 4).
