Peroxisome proliferator-activated receptor alpha: Difference between revisions

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{{Infobox gene}}
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
'''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]].<ref name="pmid7684926">{{cite journal | vauthors = Sher T, Yi HF, McBride OW, Gonzalez FJ | title = cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor | journal = Biochemistry | volume = 32 | issue = 21 | pages = 5598–604 | date = June 1993 | pmid = 7684926 | doi = 10.1021/bi00072a015 }}</ref> Together with [[peroxisome proliferator-activated receptor delta]] and [[peroxisome proliferator-activated receptor gamma]], PPAR-alpha is part of the subfamily of [[peroxisome proliferator-activated receptor]]s. 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.<ref name="pmid2129546">{{cite journal | vauthors =  Issemann I, Green S | title = Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. | journal = Nature | volume = 347 | issue = 6294 | pages = 645–54 | date = October 1990 | pmid = 2129546 | doi = 10.1038/347645a0 }}</ref>
{{GNF_Protein_box
| image = PBB_Protein_PPARA_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1i7g.
| PDB = {{PDB2|1i7g}}, {{PDB2|1k7l}}, {{PDB2|1kkq}}, {{PDB2|2p54}}
| Name = Peroxisome proliferator-activated receptor alpha
| HGNCid = 9232
| Symbol = PPARA
| AltSymbols =; MGC2237; MGC2452; NR1C1; PPAR; hPPAR
| OMIM = 170998
| ECnumber =
| Homologene = 21047
| MGIid = 104740
| GeneAtlas_image1 = PBB_GE_PPARA_206870_at_tn.png
| GeneAtlas_image2 = PBB_GE_PPARA_gnf1h00859_at_tn.png
| Function = {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0003707 |text = steroid hormone receptor activity}} {{GNF_GO|id=GO:0004872 |text = receptor activity}} {{GNF_GO|id=GO:0004879 |text = ligand-dependent nuclear receptor activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0008270 |text = zinc ion binding}} {{GNF_GO|id=GO:0016563 |text = transcription activator activity}} {{GNF_GO|id=GO:0043565 |text = sequence-specific DNA binding}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}}
| Process = {{GNF_GO|id=GO:0006350 |text = transcription}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0006366 |text = transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0006629 |text = lipid metabolic process}} {{GNF_GO|id=GO:0008544 |text = epidermis development}} {{GNF_GO|id=GO:0015908 |text = fatty acid transport}} {{GNF_GO|id=GO:0019217 |text = regulation of fatty acid metabolic process}} {{GNF_GO|id=GO:0032000 |text = positive regulation of fatty acid beta-oxidation}} {{GNF_GO|id=GO:0045941 |text = positive regulation of transcription}} {{GNF_GO|id=GO:0045944 |text = positive regulation of transcription from RNA polymerase II promoter}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 5465
    | Hs_Ensembl = ENSG00000186951
    | Hs_RefseqProtein = NP_001001929
    | Hs_RefseqmRNA = NM_001001929
    | Hs_GenLoc_db =   
    | Hs_GenLoc_chr = 22
    | Hs_GenLoc_start = 44925163
    | Hs_GenLoc_end = 45018317
    | Hs_Uniprot = Q07869
    | Mm_EntrezGene = 19013
    | Mm_Ensembl = ENSMUSG00000022383
    | Mm_RefseqmRNA = NM_011144
    | Mm_RefseqProtein = NP_035274
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 15
    | Mm_GenLoc_start = 85605326
    | Mm_GenLoc_end = 85629024
    | Mm_Uniprot = Q542P9
  }}
}}
'''Peroxisome proliferator-activated receptor alpha''' ('''PPAR-alpha'''), also known as '''NR1C1''' (nuclear receptor subfamily 1, group C, member 1), is a [[nuclear receptor]] protein encoded by the '''{{gene|PPARA}}''' gene.


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{PBB_Summary
[[File:PPARalpha transcriptome.png|thumb|Mouse liver PPARalpha transcriptome]]
| section_title =
[[File:Human hepatocyte PPARalpha transcriptome.png|thumb|Human hepatocyte PPARalpha transcriptome]]
| summary_text = Peroxisome proliferators receptor [[ligand (biochemistry)|ligand]]s include hypolipidemic drugs, herbicides, leukotriene antagonists, and plasticizers; this term arises because they induce an increase in the size and number of peroxisomes. [[Peroxisome]]s are subcellular organelles found in plants and animals that contain enzymes for respiration and for cholesterol and lipid metabolism. The action of peroxisome proliferators is thought to be mediated via specific receptors, called [[peroxisome proliferator-activated receptor|PPARs]], which belong to the steroid hormone receptor superfamily. PPARs affect the expression of target genes involved in cell proliferation, cell differentiation and in immune and inflammation responses. Three closely related subtypes (alpha, beta/delta, and gamma) have been identified. This gene encodes the subtype PPAR-alpha, which is a nuclear [[transcription factor]]. Multiple alternatively spliced transcript variants have been described for this gene, although the full-length nature of only two has been determined.<ref>{{cite web | title = Entrez Gene: PPARA peroxisome proliferator-activated receptor alpha| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5465| accessdate = }}</ref>
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.<ref name="pmid10359558">{{cite journal | vauthors = Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W | title = Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. | journal = J Clin Invest | volume = 103 | issue = 11 | pages = 1489–98 | date = June 1999 | pmid = 10359558 | pmc = 408372 | doi = 10.1172/JCI6223 }}</ref> Activation of PPAR-alpha promotes uptake, utilization, and catabolism of fatty acids by upregulation of genes involved in fatty acid transport, fatty acid binding and activation, and peroxisomal and mitochondrial fatty acid β-oxidation.<ref name="pmid24944896">{{cite journal | vauthors = Kersten S | title = Integrated physiology and systems biology of PPARα. | journal = Molecular Metabolism | volume = 3 | pages = 354–371 | year = 2014 | pmid = 24944896 | pmc = 4060217 | doi = 10.1016/j.molmet.2014.02.002 }}</ref> 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 such as [[arachidonic acid]] as well as other [[polyunsaturated fatty acids]] and various fatty acid-derived compounds such as certain members of the [[15-hydroxyicosatetraenoic acid]] family of arachidonic acid metabolites, e.g. 15(''S'')-HETE, 15(R)-HETE, and 15(S)-HpETE and [[13-hydroxyoctadecadienoic acid]], a [[linoleic acid]] metabolite.
}}


==See also==
== Tissue distribution ==
*[[Peroxisome proliferator-activated receptor]]


==References==
Expression of PPAR-alpha is highest in tissues that oxidize [[fatty acid]]s at a rapid rate. In rodents, highest [[messenger RNA|mRNA]] expression levels of PPAR-alpha are found in liver and brown adipose tissue, followed by heart and kidney.<ref name="pmid8536636">{{cite journal | vauthors = Braissant O, Foufelle F, Scotto C, Dauça M, Wahli W | title = Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. | journal = Endocrinology | volume = 137 | issue = 1 | pages = 354–66 | date = January 1995 | pmid = 8536636 | doi = 10.1210/endo.137.1.8536636 }}</ref> 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.
{{reflist|2}}
 
==Further reading==
== 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.<ref name="pmid7539101">{{cite journal | vauthors = Lee SS, Pineau T, Drago J, Lee EJ, Owens JW, Kroetz DL, Fernandez-Salguero PM, Westphal H, Gonzalez FJ | title = 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. | journal = Mol Cell Biol | volume = 15 | issue = 6 | pages = 3012–22 | date = June 1995 | pmid = 7539101 | pmc = 230532 }}</ref> 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]].<ref name="pmid10359558"/>
 
== Pharmacology ==
 
PPAR-alpha serves as cellular receptor for [[fibrate]]s, a class of drugs used in the treatment of dyslipidemia. Fibrates effectively lower serum [[triglyceride]]s and raises serum [[High-density lipoprotein|HDL]]-cholesterol levels.<ref name="pmid18628776">{{cite journal | vauthors = Staels B, Maes M, Zambon A | title = Peroxisome Fibrates and future PPARα agonists in the treatment of cardiovascular disease. | journal = Nat Clin Pract Cardiovasc Med | volume = 5 | issue = 9 | pages = 542–53 | date = September 2008 | pmid = 18628776 | doi = 10.1038/ncpcardio1278 }}</ref> 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 disease|coronary heart disease]], in contrast to [[statin]]s. 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 [[anticonvulsant]]s.<ref name="pmid23724059">{{cite journal | vauthors = Puligheddu M, Pillolla G, Melis M, Lecca S, Marrosu F, De Montis MG, Scheggi S, Carta G, Murru E, Aroni S, Muntoni AL, Pistis M | title = PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings. | journal = PLoS ONE | volume = 8 | issue = 5 | pages = e64541 | year = 2013 | pmid = 23724059 | pmc = 3664607 | doi = 10.1371/journal.pone.0064541 }}</ref><ref name="pmid23206503">{{cite journal | vauthors = Citraro R, Russo E, Scicchitano F, van Rijn CM, Cosco D, Avagliano C, Russo R, D'Agostino G, Petrosino S, Guida F, Gatta L, van Luijtelaar G, Maione S, Di Marzo V, Calignano A, De Sarro G | title = Antiepileptic action of N-palmitoylethanolamine through CB1 and PPAR-α receptor activation in a genetic model of absence epilepsy. | journal = Neuropharmacology | volume = 69 | issue =  | pages = 115–26 | year = 2013 | pmid = 23206503 | pmc =  | doi = 10.1016/j.neuropharm.2012.11.017 | url = https://www.ncbi.nlm.nih.gov/pubmed/23206503 }}</ref>
 
== 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.<ref name="pmid24944896"/>  Classical target genes of PPAR-alpha include [[PDK4]], [[ACOX1]], and [[Carnitine palmitoyltransferase I|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 [[:File:PPARalpha transcriptome.png|mouse liver]] and [[:File:Human hepatocyte PPARalpha transcriptome.png|human liver]], put PPAR-alpha at the center of a regulatory hub impacting fatty acid uptake and intracellular binding, mitochondrial [[Beta oxidation|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 [[Protein-protein interaction|interact]] with:
* [[AIP (gene)|AIP]],<ref name="pmid12482853">{{cite journal | vauthors = Sumanasekera WK, Tien ES, Turpey R, Vanden Heuvel JP, Perdew GH | title = 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 | journal = J. Biol. Chem. | volume = 278 | issue = 7 | pages = 4467–73 | date = February 2003 | pmid = 12482853 | doi = 10.1074/jbc.M211261200 }}</ref>
* [[EP300]]<ref name=pmid9407140/><ref name=pmid10336495/>
* [[Heat shock protein 90kDa alpha (cytosolic), member A1|HSP90AA1]],<ref name=pmid12482853/>
* [[Nuclear receptor coactivator 1|NCOA1]],<ref name="pmid9407140">{{cite journal | vauthors = Dowell P, Ishmael JE, Avram D, Peterson VJ, Nevrivy DJ, Leid M | title = p300 functions as a coactivator for the peroxisome proliferator-activated receptor alpha | journal = J. Biol. Chem. | volume = 272 | issue = 52 | pages = 33435–43 | date = December 1997 | pmid = 9407140 | doi = 10.1074/jbc.272.52.33435 }}</ref><ref name="pmid9626662">{{cite journal | vauthors = Treuter E, Albrektsen T, Johansson L, Leers J, Gustafsson JA | title = A regulatory role for RIP140 in nuclear receptor activation | journal = Mol. Endocrinol. | volume = 12 | issue = 6 | pages = 864–81 | date = June 1998 | pmid = 9626662 | doi = 10.1210/mend.12.6.0123 }}</ref> and
* [[Nuclear receptor co-repressor 1|NCOR1]].<ref name="pmid10336495">{{cite journal | vauthors = Dowell P, Ishmael JE, Avram D, Peterson VJ, Nevrivy DJ, Leid M | title = Identification of nuclear receptor corepressor as a peroxisome proliferator-activated receptor alpha interacting protein | journal = J. Biol. Chem. | volume = 274 | issue = 22 | pages = 15901–7 | date = May 1999 | pmid = 10336495 | doi = 10.1074/jbc.274.22.15901 }}</ref>
 
== See also ==
* [[Peroxisome proliferator-activated receptor]]
* [[Fibrate]]
 
== References ==
{{reflist}}
 
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
* {{cite journal | vauthors = Rakhshandehroo M, Hooiveld G, Müller M, Kersten S | title = Comparative analysis of gene regulation by the transcription factor PPARalpha between mouse and human. | journal = PLoS ONE | volume = 4 | pages = e6796 | year = 2009 | pmid = 19710929 | pmc = 2729378 | doi = 10.1371/journal.pone.0006796 }}
| citations =
* {{cite journal | vauthors = Berger J, Moller DE | title = The mechanisms of action of PPARs. | journal = Annu. Rev. Med. | volume = 53 | issue = | pages = 409–35 | year = 2002 | pmid = 11818483 | doi = 10.1146/annurev.med.53.082901.104018 }}
*{{cite journal | author=Berger J, Moller DE |title=The mechanisms of action of PPARs. |journal=Annu. Rev. Med. |volume=53 |issue=  |pages= 409-35 |year= 2002 |pmid= 11818483 |doi= 10.1146/annurev.med.53.082901.104018 }}
* {{cite journal | vauthors = Kuenzli S, Saurat JH | title = Peroxisome proliferator-activated receptors in cutaneous biology. | journal = Br. J. Dermatol. | volume = 149 | issue = 2 | pages = 229–36 | year = 2003 | pmid = 12932225 | doi = 10.1046/j.1365-2133.2003.05532.x }}
*{{cite journal | author=Kuenzli S, Saurat JH |title=Peroxisome proliferator-activated receptors in cutaneous biology. |journal=Br. J. Dermatol. |volume=149 |issue= 2 |pages= 229-36 |year= 2003 |pmid= 12932225 |doi= }}
* {{cite journal | vauthors = Mandard S, Müller M, Kersten S | title = Peroxisome proliferator-activated receptor alpha target genes. | journal = Cell. Mol. Life Sci. | volume = 61 | issue = 4 | pages = 393–416 | year = 2004 | pmid = 14999402 | doi = 10.1007/s00018-003-3216-3 }}
*{{cite journal | author=Mandard S, Müller M, Kersten S |title=Peroxisome proliferator-activated receptor alpha target genes. |journal=Cell. Mol. Life Sci. |volume=61 |issue= 4 |pages= 393-416 |year= 2004 |pmid= 14999402 |doi= 10.1007/s00018-003-3216-3 }}
* {{cite journal | vauthors = van Raalte DH, Li M, Pritchard PH, Wasan KM | title = Peroxisome proliferator-activated receptor (PPAR)-alpha: a pharmacological target with a promising future. | journal = Pharm. Res. | volume = 21 | issue = 9 | pages = 1531–8 | year = 2005 | pmid = 15497675 | doi = 10.1023/B:PHAM.0000041444.06122.8d }}
*{{cite journal | author=van Raalte DH, Li M, Pritchard PH, Wasan KM |title=Peroxisome proliferator-activated receptor (PPAR)-alpha: a pharmacological target with a promising future. |journal=Pharm. Res. |volume=21 |issue= 9 |pages= 1531-8 |year= 2005 |pmid= 15497675 |doi= }}
* {{cite journal | vauthors = Lefebvre P, Chinetti G, Fruchart JC, Staels B | title = Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. | journal = J. Clin. Invest. | volume = 116 | issue = 3 | pages = 571–80 | year = 2006 | pmid = 16511589 | pmc = 1386122 | doi = 10.1172/JCI27989 }}
*{{cite journal | author=Lefebvre P, Chinetti G, Fruchart JC, Staels B |title=Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. |journal=J. Clin. Invest. |volume=116 |issue= 3 |pages= 571-80 |year= 2006 |pmid= 16511589 |doi= 10.1172/JCI27989 }}
* {{cite journal | vauthors = Mukherjee R, Jow L, Noonan D, McDonnell DP | title = Human and rat peroxisome proliferator activated receptors (PPARs) demonstrate similar tissue distribution but different responsiveness to PPAR activators. | journal = J. Steroid Biochem. Mol. Biol. | volume = 51 | issue = 3–4 | pages = 157–66 | year = 1995 | pmid = 7981125 | doi = 10.1016/0960-0760(94)90089-2 }}
*{{cite journal | author=Sher T, Yi HF, McBride OW, Gonzalez FJ |title=cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor. |journal=Biochemistry |volume=32 |issue= 21 |pages= 5598-604 |year= 1993 |pmid= 7684926 |doi= }}
* {{cite journal | vauthors = Miyata KS, McCaw SE, Patel HV, Rachubinski RA, Capone JP | title = The orphan nuclear hormone receptor LXR alpha interacts with the peroxisome proliferator-activated receptor and inhibits peroxisome proliferator signaling. | journal = J. Biol. Chem. | volume = 271 | issue = 16 | pages = 9189–92 | year = 1996 | pmid = 8621574 | doi = 10.1074/jbc.271.16.9189 }}
*{{cite journal | author=Mukherjee R, Jow L, Noonan D, McDonnell DP |title=Human and rat peroxisome proliferator activated receptors (PPARs) demonstrate similar tissue distribution but different responsiveness to PPAR activators. |journal=J. Steroid Biochem. Mol. Biol. |volume=51 |issue= 3-4 |pages= 157-66 |year= 1995 |pmid= 7981125 |doi= }}
* {{cite journal | vauthors = Chu R, Lin Y, Rao MS, Reddy JK | title = Cloning and identification of rat deoxyuridine triphosphatase as an inhibitor of peroxisome proliferator-activated receptor alpha. | journal = J. Biol. Chem. | volume = 271 | issue = 44 | pages = 27670–6 | year = 1996 | pmid = 8910358 | doi = 10.1074/jbc.271.44.27670 }}
*{{cite journal | author=Miyata KS, McCaw SE, Patel HV, ''et al.'' |title=The orphan nuclear hormone receptor LXR alpha interacts with the peroxisome proliferator-activated receptor and inhibits peroxisome proliferator signaling. |journal=J. Biol. Chem. |volume=271 |issue= 16 |pages= 9189-92 |year= 1996 |pmid= 8621574 |doi= }}
* {{cite journal | vauthors = Tugwood JD, Aldridge TC, Lambe KG, Macdonald N, Woodyatt NJ | title = Peroxisome proliferator-activated receptors: structures and function. | journal = Ann. N. Y. Acad. Sci. | volume = 804 | issue =  | pages = 252–65 | year = 1997 | pmid = 8993548 | doi = 10.1111/j.1749-6632.1996.tb18620.x }}
*{{cite journal | author=Chu R, Lin Y, Rao MS, Reddy JK |title=Cloning and identification of rat deoxyuridine triphosphatase as an inhibitor of peroxisome proliferator-activated receptor alpha. |journal=J. Biol. Chem. |volume=271 |issue= 44 |pages= 27670-6 |year= 1996 |pmid= 8910358 |doi= }}
* {{cite journal | vauthors = Li H, Gomes PJ, Chen JD | title = RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2. | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 94 | issue = 16 | pages = 8479–84 | year = 1997 | pmid = 9238002 | pmc = 22964 | doi = 10.1073/pnas.94.16.8479 }}
*{{cite journal | author=Tugwood JD, Aldridge TC, Lambe KG, ''et al.'' |title=Peroxisome proliferator-activated receptors: structures and function. |journal=Ann. N. Y. Acad. Sci. |volume=804 |issue=  |pages= 252-65 |year= 1997 |pmid= 8993548 |doi= }}
* {{cite journal | vauthors = Dowell P, Ishmael JE, Avram D, Peterson VJ, Nevrivy DJ, Leid M | title = p300 functions as a coactivator for the peroxisome proliferator-activated receptor alpha. | journal = J. Biol. Chem. | volume = 272 | issue = 52 | pages = 33435–43 | year = 1998 | pmid = 9407140 | doi = 10.1074/jbc.272.52.33435 }}
*{{cite journal | author=Li H, Gomes PJ, Chen JD |title=RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=94 |issue= 16 |pages= 8479-84 |year= 1997 |pmid= 9238002 |doi= }}
* {{cite journal | vauthors = Inoue I, Shino K, Noji S, Awata T, Katayama S | title = Expression of peroxisome proliferator-activated receptor alpha (PPAR alpha) in primary cultures of human vascular endothelial cells. | journal = Biochem. Biophys. Res. Commun. | volume = 246 | issue = 2 | pages = 370–4 | year = 1998 | pmid = 9610365 | doi = 10.1006/bbrc.1998.8622 }}
*{{cite journal | author=Dowell P, Ishmael JE, Avram D, ''et al.'' |title=p300 functions as a coactivator for the peroxisome proliferator-activated receptor alpha. |journal=J. Biol. Chem. |volume=272 |issue= 52 |pages= 33435-43 |year= 1998 |pmid= 9407140 |doi= }}
* {{cite journal | vauthors = Treuter E, Albrektsen T, Johansson L, Leers J, Gustafsson JA | title = A regulatory role for RIP140 in nuclear receptor activation. | journal = Mol. Endocrinol. | volume = 12 | issue = 6 | pages = 864–81 | year = 1998 | pmid = 9626662 | doi = 10.1210/mend.12.6.0123 }}
*{{cite journal | author=Inoue I, Shino K, Noji S, ''et al.'' |title=Expression of peroxisome proliferator-activated receptor alpha (PPAR alpha) in primary cultures of human vascular endothelial cells. |journal=Biochem. Biophys. Res. Commun. |volume=246 |issue= 2 |pages= 370-4 |year= 1998 |pmid= 9610365 |doi= 10.1006/bbrc.1998.8622 }}
* {{cite journal | vauthors = Rubino D, Driggers P, Arbit D, Kemp L, Miller B, Coso O, Pagliai K, Gray K, Gutkind S, Segars J | title = Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action. | journal = Oncogene | volume = 16 | issue = 19 | pages = 2513–26 | year = 1998 | pmid = 9627117 | doi = 10.1038/sj.onc.1201783 }}
*{{cite journal | author=Treuter E, Albrektsen T, Johansson L, ''et al.'' |title=A regulatory role for RIP140 in nuclear receptor activation. |journal=Mol. Endocrinol. |volume=12 |issue= 6 |pages= 864-81 |year= 1998 |pmid= 9626662 |doi= }}
* {{cite journal | vauthors = Yuan CX, Ito M, Fondell JD, Fu ZY, Roeder RG | title = The TRAP220 component of a thyroid hormone receptor- associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand-dependent fashion. | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | issue = 14 | pages = 7939–44 | year = 1998 | pmid = 9653119 | pmc = 20908 | doi = 10.1073/pnas.95.14.7939 }}
*{{cite journal | author=Rubino D, Driggers P, Arbit D, ''et al.'' |title=Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action. |journal=Oncogene |volume=16 |issue= 19 |pages= 2513-26 |year= 1998 |pmid= 9627117 |doi= 10.1038/sj.onc.1201783 }}
* {{cite journal | vauthors = Chinetti G, Griglio S, Antonucci M, Torra IP, Delerive P, Majd Z, Fruchart JC, Chapman J, Najib J, Staels B | title = Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. | journal = J. Biol. Chem. | volume = 273 | issue = 40 | pages = 25573–80 | year = 1998 | pmid = 9748221 | doi = 10.1074/jbc.273.40.25573 }}
*{{cite journal | author=Yuan CX, Ito M, Fondell JD, ''et al.'' |title=The TRAP220 component of a thyroid hormone receptor- associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand-dependent fashion. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=95 |issue= 14 |pages= 7939-44 |year= 1998 |pmid= 9653119 |doi= }}
* {{cite journal | vauthors = Costet P, Legendre C, Moré J, Edgar A, Galtier P, Pineau T | title = Peroxisome proliferator-activated receptor alpha-isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steatosis. | journal = J. Biol. Chem. | volume = 273 | issue = 45 | pages = 29577–85 | year = 1998 | pmid = 9792666 | doi = 10.1074/jbc.273.45.29577 }}
*{{cite journal | author=Chinetti G, Griglio S, Antonucci M, ''et al.'' |title=Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. |journal=J. Biol. Chem. |volume=273 |issue= 40 |pages= 25573-80 |year= 1998 |pmid= 9748221 |doi= }}
* {{cite journal | vauthors = Masuda N, Yasumo H, Furusawa T, Tsukamoto T, Sadano H, Osumi T | title = Nuclear receptor binding factor-1 (NRBF-1), a protein interacting with a wide spectrum of nuclear hormone receptors. | journal = Gene | volume = 221 | issue = 2 | pages = 225–33 | year = 1998 | pmid = 9795230 | doi = 10.1016/S0378-1119(98)00461-2 }}
*{{cite journal | author=Costet P, Legendre C, Moré J, ''et al.'' |title=Peroxisome proliferator-activated receptor alpha-isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steatosis. |journal=J. Biol. Chem. |volume=273 |issue= 45 |pages= 29577-85 |year= 1998 |pmid= 9792666 |doi= }}
* {{cite journal | vauthors = Rakhshandehroo M, Sanderson LM, Matilainen M, Stienstra R, Carlberg C, de Groot PJ, Müller M, Kersten S | title = Comprehensive analysis of PPARalpha-dependent regulation of hepatic lipid metabolism by expression profiling. | journal = PPAR Res. | volume = 2007 | pages = 26839 | year = 2007 | pmid = 18288265 | doi = 10.1155/2007/26839 | pmc=2233741}}
*{{cite journal | author=Masuda N, Yasumo H, Furusawa T, ''et al.'' |title=Nuclear receptor binding factor-1 (NRBF-1), a protein interacting with a wide spectrum of nuclear hormone receptors. |journal=Gene |volume=221 |issue= 2 |pages= 225-33 |year= 1998 |pmid= 9795230 |doi= }}
*{{cite journal | author=Ellinghaus P, Wolfrum C, Assmann G, ''et al.'' |title=Phytanic acid activates the peroxisome proliferator-activated receptor alpha (PPARalpha) in sterol carrier protein 2-/ sterol carrier protein x-deficient mice. |journal=J. Biol. Chem. |volume=274 |issue= 5 |pages= 2766-72 |year= 1999 |pmid= 9915808 |doi= }}
}}
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Revision as of 02:53, 25 November 2017

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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

File:PPARalpha transcriptome.png
Mouse liver PPARalpha transcriptome
File:Human hepatocyte PPARalpha transcriptome.png
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 acid 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 such as arachidonic acid as well as other polyunsaturated fatty acids and various fatty acid-derived compounds such as certain members of the 15-hydroxyicosatetraenoic acid family of arachidonic acid metabolites, e.g. 15(S)-HETE, 15(R)-HETE, and 15(S)-HpETE and 13-hydroxyoctadecadienoic acid, a linoleic acid metabolite.

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. doi:10.1021/bi00072a015. PMID 7684926.
  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. doi:10.1038/347645a0. PMID 2129546.
  3. ↑ 3.0 3.1 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. doi:10.1172/JCI6223. PMC 408372. PMID 10359558.
  4. ↑ 4.0 4.1 Kersten S (2014). "Integrated physiology and systems biology of PPARα". Molecular Metabolism. 3: 354–371. doi:10.1016/j.molmet.2014.02.002. PMC 4060217. PMID 24944896.
  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. doi:10.1210/endo.137.1.8536636. PMID 8536636.
  6. ↑ Lee SS, Pineau T, Drago 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. PMC 230532. PMID 7539101.
  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. doi:10.1038/ncpcardio1278. PMID 18628776.
  8. ↑ Puligheddu M, Pillolla G, Melis M, Lecca S, Marrosu F, De Montis MG, Scheggi S, Carta G, Murru E, Aroni S, Muntoni AL, Pistis M (2013). "PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings". PLoS ONE. 8 (5): e64541. doi:10.1371/journal.pone.0064541. PMC 3664607. PMID 23724059.
  9. ↑ Citraro R, Russo E, Scicchitano F, van Rijn CM, Cosco D, Avagliano C, Russo R, D'Agostino G, Petrosino S, Guida F, Gatta L, van Luijtelaar G, Maione S, Di Marzo V, Calignano A, De Sarro G (2013). "Antiepileptic action of N-palmitoylethanolamine through CB1 and PPAR-α receptor activation in a genetic model of absence epilepsy". Neuropharmacology. 69: 115–26. doi:10.1016/j.neuropharm.2012.11.017. PMID 23206503.
  10. ↑ 10.0 10.1 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. doi:10.1074/jbc.M211261200. PMID 12482853.
  11. ↑ 11.0 11.1 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. doi:10.1074/jbc.272.52.33435. PMID 9407140.
  12. ↑ 12.0 12.1 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. doi:10.1074/jbc.274.22.15901. PMID 10336495.
  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. doi:10.1210/mend.12.6.0123. PMID 9626662.

Further reading

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

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