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