Peroxisome Proliferator-activated Receptor Alpha Mediates the Effects of High-fat Diet on Hepatic Gene Expression

Peroxisome proliferator-activated receptors (PPARs) are transcription factors involved in the regulation of numerous metabolic processes. The PPARalpha isotype is abundant in liver and activated by fasting. However, it is not very clear what other nutritional conditions activate PPARalpha. To examine whether PPARalpha mediates the effects of chronic high-fat feeding, wild-type and PPARalpha null mice were fed a low-fat diet (LFD) or high-fat diet (HFD) for 26 wk. HFD and PPARalpha deletion independently increased liver triglycerides. Furthermore, in wild-type mice HFD was associated with a significant increase in hepatic PPARalpha mRNA and plasma free fatty acids, leading to a PPARalpha-dependent increase in expression of PPARalpha marker genes CYP4A10 and CYP4A14. Microarray analysis revealed that HFD increased hepatic expression of characteristic PPARalpha target genes involved in fatty acid oxidation in a PPARalpha-dependent manner, although to a lesser extent than fasting or Wy14643. Microarray analysis also indicated functional compensation for PPARalpha in PPARalpha null mice. Remarkably, in PPARalpha null mice on HFD, PPARgamma mRNA was 20-fold elevated compared with wild-type mice fed a LFD, reaching expression levels of PPARalpha in normal mice. Adenoviral overexpression of PPARgamma in liver indicated that PPARgamma can up-regulate genes involved in lipo/adipogenesis but also characteristic PPARalpha targets involved in fatty acid oxidation. It is concluded that 1) PPARalpha and PPARalpha-signaling are activated in liver by chronic high-fat feeding; and 2) PPARgamma may compensate for PPARalpha in PPARalpha null mice on HFD.