Abstract
The peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcription factor involved in the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. PPARα serves as a molecular target for hypolipidemic fibrates drugs which bind the receptor with high affinity. Furthermore, PPARα binds and is activated by numerous fatty acids and fatty acid-derived compounds. PPARα governs biological processes by altering the expression of a large number of target genes. Accordingly, the specific role of PPARα is directly related to the biological function of its target genes. Here, we present an overview of the involvement of PPARα in lipid metabolism and other pathways through a detailed analysis of the different known or putative PPARα target genes. The emphasis is on gene regulation by PPARα in liver although many of the results likely apply to other organs and tissues as well.
Highlights
Nutrient metabolism and energy homeostasis are tightly controlled by numerous regulatory systems involving specific transcription factors
PPARα was initially isolated as a novel nuclear hormone receptor that serves as molecular target of a diverse class of rodent hepatocarcinogens
PPARα is nowadays considered as a crucial fatty acids sensor that mediates the effects of numerous fatty acids and fatty acid derivatives on gene expression
Summary
Nutrient metabolism and energy homeostasis are tightly controlled by numerous regulatory systems involving specific transcription factors. All PPARs share the same molecular mode of action via formation of heterodimers with the nuclear receptor RXR, followed by binding to specific DNA-response elements in target genes known as peroxisome proliferator response elements (PPREs). Recent studies indicate that the standard approach to screen for PPREs in the 1-2 kb region upstream of the transcriptional start site (TSS) is at odds with accumulating evidence that PPARs often bind quite distant from the TSS [12,13,14]. In those cases, contact with the basal transcription machinery is expected to be established via DNA looping. Other aspects that need to be taken into account include correspondence in gene function with better established PPAR targets and the timing of gene induction following PPARα activation
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