peroxisome proliferator activated receptor alpha
|Classification||Mus musculus » Zinc-coordinating Group » Hormone-nuclear Receptor Family » Subfamily 1 (TR, RAR, PPAR, REV-ERB, E78, RZR/ROR, CNR14, ECR, VDR, DHR96, NHR1, and 27 individual genes)|
|Related TF(s)|| • PPARA |
|Homologs ||(none defined here)|
|Links||ENSMUSG00000022383 (Ensembl) 19013 (Entrez Gene) Homologene |
|Synonyms||Ppar, PPAR-alpha, PPARalpha, Nr1c1, 4933429D07Rik, AW742785|
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PPARalpha, the first PPAR
Mouse PPAR alpha, the first PPAR to be found, was first identified due to its activity in response to peroxisome proliferators . Peroxisome proliferator-activated receptors (PPARs) are conserved lipid-activated nuclear receptors of the steroid receptor superfamily. The three different PPAR isotypes (alpha, beta/delta, gamma) share a highly conserved structure and molecular mechanism of action . PPARs are lipid-activated nuclear receptors and as such refered to as metabolic sensors . Nevertheless, they differ in their ligand selectivity  and target genes . PPARs can be activated by different synthetic chemicals ranging from endogenous lipids, hypolipidemic drugs, herbicides, leukotriene antagonists, and plasticizers . It is thus a major target for environmental polluants .
PPARalpha expression is found from late embryogenesis on in mouse . In adults, PPARalpha is most expressed in tissues with high fatty acid beta-oxidation (i.e. liver, cardiac and skeletal muscle) where it controls the expression of beta-oxidation genes. PPARalpha is also found in the gastrointestinal tract, kidney and brown adipose tissue .
Functions: metabolism and inflammation
PPARalpha is a key regulator of metabolism as it is involved in control of liver glucose metabolism, lipid metabolism and in the switch toward lipid metabolism under fasting conditions.
Indeed in liver, PPARalpha is required for energy production from fatty acids stores by controlling the expression of beta-oxydation enzymes in the liver. PPARalpha also regulates pyruvate utilization toward gluconeogenesis.
PPARalpha-null mice do not display obvious phenotype under normal diet and husbandry conditions . Nevertheless, overtime, PPARalpha-null mice tend to increase their stores of fatty acids . Notably, it’s upon fasting that PPARalpha function in liver is essential . Indeed, fasting induces transfer of fatty acids from the adipose tissue to the liver where they are oxidized to provide energy. In absence of PPARalpha, fatty acids are transported to the liver where they fail to be oxidized due to the non-induction of the necessary enzymes by PPARalpha.
Oleylethanolamide, a naturally occurring lipid, is able to activate PPARalpha leading to satiety, resulting in control of body weight in mice .
Besides its role in metabolism, PPARalpha is a major player of inflammation where it serves as a receptor for Leukotriene B4 a chemotactant that coordinates, sustains and amplifies the inflammatory response  and absence of PPARalpha leads to delay in skin wound healing due to impared inflammation .
PPARalpha, like all PPARs, requires heterodimerization with RXR to transactivate genes expression. The PPARalpha/RXR heterodimer binds to DNA on the Peroxisome Proliferator Response Element (PPRE) in the promoter region of target genes. The consensus PPRE are direct repeat of the consensus AGGTCA sequence spaced with 1 nucleotide (DR1). Upon ligand activation the helix-12 of PPARalpha ligand-binding domain is positioned into an active conformation, triggering target genes transactivation. Depending whether they are full agonist (i.e. fenofibrates) or partial agonists (i.e. DEHP), the ligands trigger different response of PPARalpha in term of transactivation. The reason for that is unclear yet but may come from differential cofactors recruitment.
Due to its major roles in fatty acid and carbohydrate metabolism regulation, PPARalpha has been a focus for pharmacological treatment of the metabolic syndrome, obesity and diabetis . Indeed, PPARalpha ligand such as the hypolipidemic fibrates are used to treat the metabolic syndrome and result in a better insuline sensitivity and lowering of cholesterol levels (both LDL and VLDL . Another important aspect of PPARalpha biology is its sensibility to endocrine disruptors such as phtalates, found in most plastics such as food packages . Thus suggesting a potential direct environmental interference with PPARalpha function.
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- Desvergne B et al. PPAR-mediated activity of phthalates: A link to the obesity epidemic? Mol. Cell. Endocrinol., 304(1-2):43-8. (PMID 19433246)
- Casals-Casas C et al. Interference of pollutants with PPARs: endocrine disruption meets metabolism. , 32 Suppl 6:S53-61. (PMID 19079281)
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- Aoyama T et al. Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha). J. Biol. Chem., 273(10):5678-84. (PMID 9488698)
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- Lee SS et al. Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol. Cell. Biol., 15(6):3012-22. (PMID 7539101)
- Gonzalez FJ. Recent update on the PPAR alpha-null mouse. Biochimie, 79(2-3):139-44. (PMID 9209711)
- Kersten S et al. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J. Clin. Invest., 103(11):1489-98. (PMID 10359558)
- Leone TC et al. A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. Proc. Natl. Acad. Sci. U.S.A., 96(13):7473-8. (PMID 10377439)
- Fu J et al. Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature, 425(6953):90-3. (PMID 12955147)
- Devchand PR et al. The PPARalpha-leukotriene B4 pathway to inflammation control. Nature, 384(6604):39-43. (PMID 8900274)
- Michalik L et al. Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR)alpha and PPARbeta mutant mice. J. Cell Biol., 154(4):799-814. (PMID 11514592)
- Lefebvre P et al. Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J. Clin. Invest., 116(3):571-80. (PMID 16511589)
- Wysocki J et al. Effects of micronized fenofibrate on insulin resistance in patients with metabolic syndrome. , 42(4):212-7. (PMID 15124979)
FIGURE 1 Schematic representation of mouse PPAR alpha protein domains
Like other Nuclear Receptors, Ppara has a well defined modular organization
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.
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