Abstract
In mammalian cells, two cellular organelles, mitochondria and peroxisomes, share the ability to degrade fatty acid chains. Although each organelle harbors its own fatty acid β-oxidation pathway, a distinct mitochondrial system feeds the oxidative phosphorylation pathway for ATP synthesis. At the same time, the peroxisomal β-oxidation pathway participates in cellular thermogenesis. A scientific milestone in 1965 helped discover the hepatomegaly effect in rat liver by clofibrate, subsequently identified as a peroxisome proliferator in rodents and an activator of the peroxisomal fatty acid β-oxidation pathway. These peroxisome proliferators were later identified as activating ligands of Peroxisome Proliferator-Activated Receptor α (PPARα), cloned in 1990. The ligand-activated heterodimer PPARα/RXRα recognizes a DNA sequence, called PPRE (Peroxisome Proliferator Response Element), corresponding to two half-consensus hexanucleotide motifs, AGGTCA, separated by one nucleotide. Accordingly, the assembled complex containing PPRE/PPARα/RXRα/ligands/Coregulators controls the expression of the genes involved in liver peroxisomal fatty acid β-oxidation. This review mobilizes a considerable number of findings that discuss miscellaneous axes, covering the detailed expression pattern of PPARα in species and tissues, the lessons from several PPARα KO mouse models and the modulation of PPARα function by dietary micronutrients.
Highlights
As reported in the review by Latruffe and Vamecq [1], peroxisomes are ubiquitous, single membrane-bound organelles
Repressors that bind to the nuclear receptor Peroxisome Proliferator-Activated Receptor α (PPARα) in the absence of/or independent of ligands prevent it from binding to the peroxisomal proliferator response elements (PPRE) of the target genes as nuclear corepressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone (SMRT) [96] (Figure 7A)
We have identified almost all these groups of coregulators using either a direct protein–protein interaction assay, such as a yeast two-hybrid assay [150], GST-pull downs [124], and ligand affinity chromatography [141] to identify the PPARα-interacting proteins and a functional transcriptional activation complex [131]
Summary
As reported in the review by Latruffe and Vamecq [1], peroxisomes are ubiquitous, single membrane-bound organelles They belong to the fundamental class of intracellular compartments named microbodies. Microbodies and eukaryotic cells appeared on Earth around 1.5 billion years ago Based on their related cell origin, these organelles are defined as glycosomes, glyoxysomes, hydrogenosomes or peroxisomes. Peroxisomes are found in higher vertebrates; glycosomes exist only in trypanosomes; glyoxysomes are found in leaves and seeds; hydrogenosomes are found in anaerobic unicellular ciliates, flagellates, and fungi. The latter two microbody structures belong to lower eukaryotic species, and all these compartments metabolize hydrogen peroxide. PPARs evolved three times faster than other members of the hormone nuclear receptor superfamily, and are represented in three isoforms (α, β/δ, and γ)
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