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[[Peroxisome Proliferator-Activated Receptors]] (PPARs) consist of a superfamily of nuclear hormone receptors that act as transcription factors. PPARs are ligand-activated transcription factors that govern numerous biological processes, including energy metabolism, cell proliferation and inflammation <ref name="PPAR1">PMID:12007538</ref>. PPAR-alpha is one of the three PPAR isotypes (alpha, beta and gamma), which can be distinguished by its activating ligand and its specific PPAR-regulated genes to which it provides transcriptional control.  PPAR-alpha has an important role in the regulation of nutrient metabolism, including fatty acid oxidation, gluconeogenesis and amino acid metabolism <ref name="PPAR2">PMID:10359558</ref>. PPAR-alpha is predominately expressed in tissues with high rates of mitochondrial beta oxidation, such as liver, heart, muscle, kidney and cells of the arterial wall <ref name="PPAR3">PMID:11135616</ref>. Various activating molecules of PPAR alpha have consisted of fibrates, fatty acids and eicosanoids, 15-d Ptg (15-Deoxy-Delta Prostaglandin-J2) and oxidized fatty acids. As PPAR-alpha (as well as the other associated isotypes) has an important role in the regulation of energy metabolism, and as its activity can be manipulated by various drugs, there is an increasing interest in the potential connection between PPAR alpha and obesity <ref name="PPAR1"/>.  

==Structure==

PPAR-alpha structure shares common characteristics with the other isoforms in this nuclear receptor superfamily, as it displays five distinguishable domains designated the A/B, C, D, E and F domains. The A/B domain, on the N-terminus of PPAR-alpha, contains an activation function region (AF-1), which has a low level of basal transcriptional activity and functions independently of ligand-binding. The DNA binding domain (C) contains two very highly conserved zinc finger motifs and architectural elements capable of sequence-specific binding to DNA <ref name="PPAR4">PMID:10529898</ref>. A flexible hinge region (D) connects the DNA binding domain to the ligand-binding domain (E). The ligand-binding domain in the human PPAR alpha protein contains the activation function-2 (AF-2) region composed of two alpha helices flanking one four-sided beta sheet <ref name="PPAR4"/>. Following ligand interaction, the AF-2 domain undergoes a conformational change which promotes the hydrogen bonding between Tyr-314 and Tyr-464, as well as the formation of the “charge clamp” between Glu-462 and Lys-292 <ref name="PPAR5">PMID:11698662</ref>.

==Ligand Interactions==

Within the ligand-binding domain (LBD) of PPAR alpha is a large pocket of approximately 1,400 Å, into which a small molecule ligand is bound. The ligand adopts a conformation within the receptor that allows an acidic head group to form hydrogen bonds with Tyr-314 and Tyr-464 on the AF-2 helix <ref name="PPAR7">PMID:11698662</ref>. These interactions stabilize the AF-2 helix in a conformation that generates the “charge clamp.” A major determinant of selectivity between the PPAR isotypes alpha and beta is the substitution or Tyr-314 in PPAR alpha for His-323 in PPAR beta. Although all three PPAR subtypes bind to polyunsaturated fatty acids with micromolar affinity, only PPAR alpha has been observed to bind a wide range of saturated fatty acids <ref name="PPAR7"/>.

==Function==

[[Image: PPAR_Mechanism.png|400px|right|thumb|Figure 2: Mechanism of Human PPARα & PPARγ]]