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Peroxisome proliferator-activated receptor alpha

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Title: Peroxisome proliferator-activated receptor alpha  
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Subject: Peroxisome proliferator-activated receptor gamma, Nuclear receptor, PPAR agonist, Oleoylethanolamide, Palmitoylethanolamide
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Peroxisome proliferator-activated receptor alpha

Peroxisome proliferator-activated receptor alpha

PDB rendering based on 1i7g.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols  ; NR1C1; PPAR; PPARalpha; hPPAR
External IDs IUPHAR: ChEMBL: GeneCards:
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
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PubMed search

Peroxisome proliferator-activated receptor alpha (PPAR-alpha), also known as NR1C1 (nuclear receptor subfamily 1, group C, member 1), is a nuclear receptor protein that in humans is encoded by the PPARA gene.[1] Together with Peroxisome proliferator-activated receptor delta and Peroxisome proliferator-activated receptor gamma, PPAR-alpha is part of the subfamily of Peroxisome proliferator-activated receptors. It was the first member of the PPAR family to be cloned in 1990 by Stephen Green and has been identified as the nuclear receptor for a diverse class of rodent hepatocarcinogens that causes proliferation of peroxisomes.[2]

Function

Mouse liver PPARalpha transcriptome
Human hepatocyte PPARalpha transcriptome

PPAR-alpha is a transcription factor and a major regulator of lipid metabolism in the liver. PPAR-alpha is activated under conditions of energy deprivation and is necessary for the process of ketogenesis, a key adaptive response to prolonged fasting.[3] Activation of PPAR-alpha promotes uptake, utilization, and catabolism of fatty acids by upregulation of genes involved in fatty acid transport, fatty binding and activation, and peroxisomal and mitochondrial fatty acid β-oxidation.[4] PPAR-alpha is primarily activated through ligand binding. Synthetic ligands include the fibrate drugs, which are used to treat hyperlipidemia, and a diverse set of insecticides, herbicides, plasticizers, and organic solvents collectively referred to as peroxisome proliferators. Endogenous ligands include fatty acids and various fatty acid-derived compounds.

Tissue distribution

Expression of PPAR-alpha is highest in tissues that oxidize fatty acids at a rapid rate. In rodents, highest mRNA expression levels of PPAR-alpha are found in liver and brown adipose tissue, followed by heart and kidney.[5] Lower PPAR-alpha expression levels are found in small and large intestine, skeletal muscle and adrenal gland. Human PPAR-alpha seems to be expressed more equally among various tissues, with high expression in liver, intestine, heart, and kidney.

Knock-out studies

Studies using mice lacking functional PPAR-alpha indicate that PPAR-alpha is essential for induction of peroxisome proliferation by a diverse set of synthetic compounds referred to as peroxisome proliferators.[6] Mice lacking PPAR-alpha also have an impaired response to fasting, characterized by major metabolic perturbations including low plasma levels of ketone bodies, hypoglycemia, and fatty liver.[3]

Pharmacology

PPAR-alpha serves as cellular receptor for fibrates, a class of drugs used in the treatment of dyslipidemia. Fibrates effectively lower serum triglycerides and raises serum HDL-cholesterol levels.[7] Although clinical benefits of fibrate treatment have been observed, the overall results are mixed and have led to reservations about the broad application of fibrates for the treatment of coronary heart disease, in contrast to statins. PPAR-alpha agonists may carry therapeutic value for the treatment of Non-alcoholic fatty liver disease. PPAR-alpha may also be a site of action of certain anticonvulsants [8][9]

Target genes

PPAR-alpha governs biological processes by altering the expression of a large number of target genes. Accordingly, the functional role of PPAR-alpha is directly related to the biological function of its target genes. Gene expression profiling studies have indicated that PPAR-alpha target genes number in the hundreds.[4] Classical target genes of PPAR-alpha include PDK4, ACOX1, and CPT1. Low and high throughput gene expression analysis have allowed the creation of comprehensive maps illustrating the role of PPAR-alpha as master regulator of lipid metabolism via regulation of numerous genes involved in various aspects of lipid metabolism. The maps, constructed for mouse liver and human liver, put PPAR-alpha at the center of a regulatory hub impacting fatty acid uptake and intracellular binding, mitochondrial β-oxidation and peroxisomal fatty acid oxidation, ketogenesis, triglyceride turnover, gluconeogenesis, and bile synthesis/secretion.

Interactions

Peroxisome proliferator-activated receptor alpha has been shown to interact with:

See also

References

  1. ^ Sher T, Yi HF, McBride OW, Gonzalez FJ (June 1993). "cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor". Biochemistry 32 (21): 5598–604.  
  2. ^ Issemann I, Green S. (October 1990). "Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators.". Nature 347 (6294): 645–54.  
  3. ^ a b Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W. (June 1999). "Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting.". J Clin Invest. 103 (11): 1489–98.  
  4. ^ a b Kersten S. (2014). "Integrated physiology and systems biology of PPARα.". Molecular Metabolism 3: 354–371.  
  5. ^ Braissant O, Foufelle F, Scotto C, Dauça M, Wahli W. (January 1995). "Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat.". Endocrinology 137 (1): 354–66.  
  6. ^ Lee SS, Pineau T, Droga J, Lee EJ, Owens JW, Kroetz DL, Fernandez-Salguero PM, Westphal H, Gonzalez FJ. (June 1995). "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.  
  7. ^ Staels B, Maes M, Zambon A. (September 2008). "Peroxisome Fibrates and future PPARα agonists in the treatment of cardiovascular disease.". Nat Clin Pract Cardiovasc Med. 5 (9): 542–53.  
  8. ^ Puligheddu M, Pillolla G, Melis M, Lecca S, Marrosu F, De Montis MG et al. (2013). "PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings.". PLoS ONE 8 (5): e64541.  
  9. ^ Citraro R, Russo E, Scicchitano F, van Rijn CM, Cosco D, Avagliano C et al. (2013). "Antiepileptic action of N-palmitoylethanolamine through CB1 and PPAR-α receptor activation in a genetic model of absence epilepsy.". Neuropharmacology 69: 115–26.  
  10. ^ a b Sumanasekera WK, Tien ES, Turpey R, Vanden Heuvel JP, Perdew GH (February 2003). "Evidence that peroxisome proliferator-activated receptor alpha is complexed with the 90-kDa heat shock protein and the hepatitis virus B X-associated protein 2". J. Biol. Chem. 278 (7): 4467–73.  
  11. ^ a b Dowell P, Ishmael JE, Avram D, Peterson VJ, Nevrivy DJ, Leid M (December 1997). "p300 functions as a coactivator for the peroxisome proliferator-activated receptor alpha". J. Biol. Chem. 272 (52): 33435–43.  
  12. ^ a b Dowell P, Ishmael JE, Avram D, Peterson VJ, Nevrivy DJ, Leid M (May 1999). "Identification of nuclear receptor corepressor as a peroxisome proliferator-activated receptor alpha interacting protein". J. Biol. Chem. 274 (22): 15901–7.  
  13. ^ Treuter E, Albrektsen T, Johansson L, Leers J, Gustafsson JA (June 1998). "A regulatory role for RIP140 in nuclear receptor activation". Mol. Endocrinol. 12 (6): 864–81.  

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.


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