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