The Relationship Between KLF5 and PPARα in the Heart It’s Complicated

The heart consumes a significant amount of ATP to maintain its contractile performance, and fatty acid oxidation (FAO) serves as a primary source of energy in the adult heart. Research in the past several decades has demonstrated that the nuclear receptor family, in particular peroxisome proliferator–activated receptor α (PPARα), is a major transcriptional mechanism regulating expression of proteins involved in fatty acid metabolism. Although much progress has been made in understanding the functional role of PPARα in cardiac physiology and disease, less is known about the regulation of PPARα itself.1 PPARα-mediated transcriptional cascades are determined by the level of PPARα expression as well as its activity. Long chain fatty acids and synthetic ligands, such as fibrates, increase the transcriptional activity of PPARα in multiple cell types, including cardiac myocytes. The endogenous ligands of PPARα are still debated but evidence indicates that they may be associated with triglyceride lipolysis.2–4 Expression of PPARα in the heart changes during the development, and under multiple pathological conditions, including heart failure and diabetes mellitus. However, the mechanism(s) underlying these changes are poorly understood. In this issue of Circulation Research , Drosatos et al5 report that Kruppel-like factor 5 (KLF5) regulates the transcription of PPARα in the heart (Figure). Figure. Peroxisome proliferator–activated receptor α (PPARα) expression and fatty acid oxidation (FAO) in the heart: proposed regulation by Kruppel-like factor 5 (KLF5), sepsis, and diabetes mellitus. PPARα level and the availability of its ligands regulate the expression of key proteins for fatty acids transport and FAO in the heart. Alterations in FAO act through feedback mechanisms to regulate PPARα expression and restore FAO to optimal levels. Deletion of KLF5 in the heart resulted in lower PPARα expression and decreased FAO. PPARα transcript levels are reduced in parallel to reduced KLF5 expression in …