Peroxisome proliferator-activated receptor alpha

PPARA
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1I7G, 1K7L, 1KKQ, 2NPA, 2P54, 2REW, 2ZNN, 3ET1, 3FEI, 3G8I, 3KDT, 3KDU, 3SP6, 3VI8, 4BCR, 4CI4, 5AZT
Identifiers
Aliases	PPARA, NR1C1, PPAR, PPARalpha, hPPAR, peroxisome proliferator activated receptor alpha, PPAR-alpha
External IDs	MGI: 104740; HomoloGene: 21047; GeneCards: PPARA; OMA:PPARA - orthologs
Gene location (Human) Chr. Chromosome 22 (human)[1] Band 22q13.31 Start 46,150,521 bp[1] End 46,243,755 bp[1]
Gene location (Mouse) Chr. Chromosome 15 (mouse)[2] Band 15 E2|15 40.42 cM Start 85,619,184 bp[2] End 85,687,020 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in renal medulla jejunal mucosa biceps brachii Skeletal muscle tissue of biceps brachii right lobe of liver retinal pigment epithelium muscle of thigh right ventricle body of tongue mucosa of sigmoid colon Top expressed in left lobe of liver right kidney intercostal muscle brown adipose tissue digastric muscle human kidney sternocleidomastoid muscle thoracic diaphragm soleus muscle transitional epithelium of urinary bladder More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA binding sequence-specific DNA binding protein domain specific binding DNA-binding transcription factor activity zinc ion binding DNA-binding transcription activator activity, RNA polymerase II-specific metal ion binding RNA polymerase II cis-regulatory region sequence-specific DNA binding steroid hormone receptor activity DNA-binding transcription repressor activity, RNA polymerase II-specific nuclear receptor activity protein binding ubiquitin conjugating enzyme binding lipid binding transcription factor binding DNA-binding transcription factor activity, RNA polymerase II-specific signaling receptor activity protein-containing complex binding transcription coactivator binding phosphatase binding NFAT protein binding MDM2/MDM4 family protein binding transcription cis-regulatory region binding RNA polymerase II transcription regulatory region sequence-specific DNA binding fatty acid binding nuclear receptor coactivator activity Cellular component nucleus nucleoplasm RNA polymerase II transcription regulator complex Biological process lipoprotein metabolic process negative regulation of pri-miRNA transcription by RNA polymerase II positive regulation of fatty acid beta-oxidation negative regulation of glycolytic process response to hypoxia regulation of transcription, DNA-templated negative regulation of blood pressure lipid metabolism rhythmic process wound healing negative regulation of leukocyte cell-cell adhesion negative regulation of transcription by RNA polymerase II fatty acid transport negative regulation of protein binding negative regulation of appetite circadian regulation of gene expression transcription, DNA-templated fatty acid metabolic process behavioral response to nicotine positive regulation of transcription, DNA-templated negative regulation of cholesterol storage response to insulin heart development intracellular receptor signaling pathway negative regulation of transcription regulatory region DNA binding negative regulation of sequestering of triglyceride regulation of circadian rhythm regulation of fatty acid metabolic process epidermis development regulation of gene expression enamel mineralization positive regulation of gluconeogenesis transcription initiation from RNA polymerase II promoter negative regulation of inflammatory response negative regulation of macrophage derived foam cell differentiation positive regulation of transcription by RNA polymerase II steroid hormone mediated signaling pathway negative regulation of neuron death positive regulation of fatty acid oxidation regulation of lipid metabolic process signal transduction multicellular organism development hormone-mediated signaling pathway cell differentiation response to lipid negative regulation of transcription, DNA-templated negative regulation of cell growth involved in cardiac muscle cell development Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5465 19013 Ensembl ENSG00000186951 ENSMUSG00000022383 UniProt Q07869 Q86SF0 P23204 RefSeq (mRNA) NM_001001928 NM_001001929 NM_001001930 NM_005036 NM_032644 NM_001362872 NM_001362873 NM_001393941 NM_001393942 NM_001393943 NM_001393944 NM_001393945 NM_001393946 NM_001393947 NM_001113418 NM_011144 RefSeq (protein) NP_001001928 NP_005027 NP_001349801 NP_001349802 NP_001106889 NP_035274 Location (UCSC) Chr 22: 46.15 – 46.24 Mb Chr 15: 85.62 – 85.69 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Peroxisome proliferator-activated receptor alpha (PPAR-α), also known as NR1C1 (nuclear receptor subfamily 1, group C, member 1), is a nuclear receptor protein functioning as a transcription factor that in humans is encoded by the PPARA gene.^[5] 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.^[6]

Expression

PPAR-α is primarily activated through ligand binding. 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-hydroxyeicosatetraenoic 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. 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.

Function

Mouse liver PPARalpha transcriptome

Human hepatocyte PPARalpha transcriptome

PPAR-α is a transcription factor regulated by free fatty acids, and is a major regulator of lipid metabolism in the liver.^[7] PPAR-alpha is activated under conditions of energy deprivation and is necessary for the process of ketogenesis, a key adaptive response to prolonged fasting.^[8][9] 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.^[10] Activation of fatty acid oxidation is facilitated by increased expression of CPT1 (which brings long-chain lipids into mitochondria) by PPAR-α.^[11] PPAR-α also inhibits glycolysis, while promoting liver gluconeogenesis and glycogen synthesis.^[7]

In macrophages, PPAR-α inhibits the uptake of glycated low-density lipoprotein (LDL cholesterol), inhibits foam cell (atherosclerosis) formation, and inhibits pro-inflammatory cytokines.^[11]

Tissue distribution

Expression of PPAR-α 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.^[12] 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.

Knockout studies

Studies using mice lacking functional PPAR-alpha indicate that PPAR-α is essential for induction of peroxisome proliferation by a diverse set of synthetic compounds referred to as peroxisome proliferators.^[13] 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.^[8]

Pharmacology

PPAR-α is the pharmaceutical target of fibrates, a class of drugs used in the treatment of dyslipidemia. Fibrates effectively lower serum triglycerides and raises serum HDL-cholesterol levels.^[14] 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-α, 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.^[15][16]

An endogenous compound, 7(S)-Hydroxydocosahexaenoic Acid (7(S)-HDHA/"7-HDoHE". PubChem. National Center for Biotechnology Information.), which is a Docosanoid derivative of the omega-3 fatty acid DHA was isolated as an endogenous high affinity ligand for PPAR-alpha in the rat and mouse brain. The 7(S) enantiomer bound with micromolar affity to PPAR alpha with 10 fold higher affinity compared to the (R) enantiomer and could trigger dendritic activation.^[17] Previous evidence for the compound's function was speculative based on the structure and study of the chemical synthesis.^[18]

Both high sugar and low protein diets elevate the circulating liver hormone FGF21 in humans by means of PPAR-α, although this effect can be accompanied by FGF21-resistance.^[19]

Target genes

PPAR-α 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.^[10] 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. These 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

PPAR-α has been shown to interact with:

• AIP,^[20]
• EP300^[21][22]
• HSP90AA1,^[20]
• NCOA1,^[21][23] and
• NCOR1.^[22]
• Palmitoylethanolamide (PEA)
• Oleoylethanolamide (OEA)
• Anandamide (AEA)
• 7( S)-Hydroxydocosahexaenoic Acid (7-HDoHE)^[17]
• PFAS^[24]

See also

• Peroxisome proliferator-activated receptor
• Fibrate
• Endocannabinoid system

References

1. GRCh38: Ensembl release 89: ENSG00000186951 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000022383 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. 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.
6. Issemann I, Green S (October 1990). "Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators". Nature. 347 (6294): 645–54. Bibcode:1990Natur.347..645I. doi:10.1038/347645a0. PMID 2129546. S2CID 4306126.
7. Peeters A, Baes M (2010). "Role of PPARα in Hepatic Carbohydrate Metabolism". PPAR Research. 2010: 572405. doi:10.1155/2010/572405. PMC 2948921. PMID 20936117.
8. 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.
9. Grabacka M, Pierzchalska M, Dean M, Reiss K (2016). "Regulation of Ketone Body Metabolism and the Role of PPARα". International Journal of Molecular Sciences. 17 (12): E2093. doi:10.3390/ijms17122093. PMC 5187893. PMID 27983603.
10. Kersten S (2014). "Integrated physiology and systems biology of PPARα". Molecular Metabolism. 3 (4): 354–371. doi:10.1016/j.molmet.2014.02.002. PMC 4060217. PMID 24944896.
11. Rigamonti E, Chinetti-Gbaguidi G, Staels B (2008). "Regulation of macrophage functions by PPAR-alpha, PPAR-gamma, and LXRs in mice and men". Arteriosclerosis, Thrombosis, and Vascular Biology. 28 (6): 1050–1059. doi:10.1161/ATVBAHA.107.158998. PMID 18323516. S2CID 26425698.
12. 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.
13. Lee SS, Pineau T, Drago J, Lee EJ, Owens JW, Kroetz DL, et al. (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. doi:10.1128/MCB.15.6.3012. PMC 230532. PMID 7539101.
14. 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. S2CID 23332777.
15. 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. Bibcode:2013PLoSO...864541P. doi:10.1371/journal.pone.0064541. PMC 3664607. PMID 23724059.
16. 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. doi:10.1016/j.neuropharm.2012.11.017. PMID 23206503. S2CID 27701532.
17. Liu J, Sahin C, Ahmad S, Magomedova L, Zhang M, Jia Z, et al. (July 2022). "The omega-3 hydroxy fatty acid 7(S)-HDHA is a high-affinity PPARα ligand that regulates brain neuronal morphology". Science Signaling. 15 (741): eabo1857. doi:10.1126/scisignal.abo1857. PMID 35857636.
18. Zhang M, Sayyad AA, Dhesi A, Orellana A (November 2020). "Enantioselective Synthesis of 7(S)-Hydroxydocosahexaenoic Acid, a Possible Endogenous Ligand for PPARα". J Org Chem. 85 (21): 13621–13629. doi:10.1021/acs.joc.0c01770. PMID 32954732. S2CID 221825661.
19. Flippo KH, Potthoff MJ (2021). "Metabolic Messengers: FGF21". Nature Metabolism. 3 (3): 309–317. doi:10.1038/s42255-021-00354-2. PMC 8620721. PMID 33758421.
20. 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.
21. 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.
22. 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.
23. 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.
24. Wolf CJ, Schmid JE, Lau C, Abbott BD (July 2012). "Activation of mouse and human peroxisome proliferator-activated receptor-alpha (PPARα) by perfluoroalkyl acids (PFAAs): further investigation of C4-C12 compounds". Reproductive Toxicology. 33 (4): 546–551. Bibcode:2012RepTx..33..546W. doi:10.1016/j.reprotox.2011.09.009. PMID 22107727.

Further reading

• Rakhshandehroo M, Hooiveld G, Müller M, Kersten S (2009). "Comparative analysis of gene regulation by the transcription factor PPARalpha between mouse and human". PLOS ONE. 4 (8): e6796. Bibcode:2009PLoSO...4.6796R. doi:10.1371/journal.pone.0006796. PMC 2729378. PMID 19710929.
• Berger J, Moller DE (2002). "The mechanisms of action of PPARs". Annu. Rev. Med. 53: 409–35. doi:10.1146/annurev.med.53.082901.104018. PMID 11818483.
• Kuenzli S, Saurat JH (2003). "Peroxisome proliferator-activated receptors in cutaneous biology". Br. J. Dermatol. 149 (2): 229–36. doi:10.1046/j.1365-2133.2003.05532.x. PMID 12932225. S2CID 644071.
• Mandard S, Müller M, Kersten S (2004). "Peroxisome proliferator-activated receptor alpha target genes". Cell. Mol. Life Sci. 61 (4): 393–416. doi:10.1007/s00018-003-3216-3. PMC 11138883. PMID 14999402. S2CID 39380100.
• van Raalte DH, Li M, Pritchard PH, Wasan KM (2005). "Peroxisome proliferator-activated receptor (PPAR)-alpha: a pharmacological target with a promising future". Pharm. Res. 21 (9): 1531–8. doi:10.1023/B:PHAM.0000041444.06122.8d. PMID 15497675. S2CID 24728859.
• Lefebvre P, Chinetti G, Fruchart JC, Staels B (2006). "Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis". J. Clin. Invest. 116 (3): 571–80. doi:10.1172/JCI27989. PMC 1386122. PMID 16511589.
• Mukherjee R, Jow L, Noonan D, McDonnell DP (1995). "Human and rat peroxisome proliferator activated receptors (PPARs) demonstrate similar tissue distribution but different responsiveness to PPAR activators". J. Steroid Biochem. Mol. Biol. 51 (3–4): 157–66. doi:10.1016/0960-0760(94)90089-2. PMID 7981125. S2CID 28301985.
• Miyata KS, McCaw SE, Patel HV, Rachubinski RA, Capone JP (1996). "The orphan nuclear hormone receptor LXR alpha interacts with the peroxisome proliferator-activated receptor and inhibits peroxisome proliferator signaling". J. Biol. Chem. 271 (16): 9189–92. doi:10.1074/jbc.271.16.9189. PMID 8621574.
• Chu R, Lin Y, Rao MS, Reddy JK (1996). "Cloning and identification of rat deoxyuridine triphosphatase as an inhibitor of peroxisome proliferator-activated receptor alpha". J. Biol. Chem. 271 (44): 27670–6. doi:10.1074/jbc.271.44.27670. PMID 8910358.
• Tugwood JD, Aldridge TC, Lambe KG, Macdonald N, Woodyatt NJ (1997). "Peroxisome proliferator-activated receptors: structures and function". Ann. N. Y. Acad. Sci. 804: 252–65. doi:10.1111/j.1749-6632.1996.tb18620.x. PMID 8993548. S2CID 84519126.
• Li H, Gomes PJ, Chen JD (1997). "RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2". Proc. Natl. Acad. Sci. U.S.A. 94 (16): 8479–84. Bibcode:1997PNAS...94.8479L. doi:10.1073/pnas.94.16.8479. PMC 22964. PMID 9238002.
• Dowell P, Ishmael JE, Avram D, Peterson VJ, Nevrivy DJ, Leid M (1998). "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.
• Inoue I, Shino K, Noji S, Awata T, Katayama S (1998). "Expression of peroxisome proliferator-activated receptor alpha (PPAR alpha) in primary cultures of human vascular endothelial cells". Biochem. Biophys. Res. Commun. 246 (2): 370–4. doi:10.1006/bbrc.1998.8622. PMID 9610365.
• Treuter E, Albrektsen T, Johansson L, Leers J, Gustafsson JA (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.
• Rubino D, Driggers P, Arbit D, Kemp L, Miller B, Coso O, et al. (1998). "Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action". Oncogene. 16 (19): 2513–26. doi:10.1038/sj.onc.1201783. PMID 9627117.
• Yuan CX, Ito M, Fondell JD, Fu ZY, Roeder RG (1998). "The TRAP220 component of a thyroid hormone receptor- associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand-dependent fashion". Proc. Natl. Acad. Sci. U.S.A. 95 (14): 7939–44. Bibcode:1998PNAS...95.7939Y. doi:10.1073/pnas.95.14.7939. PMC 20908. PMID 9653119.
• Chinetti G, Griglio S, Antonucci M, Torra IP, Delerive P, Majd Z, et al. (1998). "Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages". J. Biol. Chem. 273 (40): 25573–80. doi:10.1074/jbc.273.40.25573. PMID 9748221.
• Costet P, Legendre C, Moré J, Edgar A, Galtier P, Pineau T (1998). "Peroxisome proliferator-activated receptor alpha-isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steatosis". J. Biol. Chem. 273 (45): 29577–85. doi:10.1074/jbc.273.45.29577. PMID 9792666.
• Masuda N, Yasumo H, Furusawa T, Tsukamoto T, Sadano H, Osumi T (1998). "Nuclear receptor binding factor-1 (NRBF-1), a protein interacting with a wide spectrum of nuclear hormone receptors". Gene. 221 (2): 225–33. doi:10.1016/S0378-1119(98)00461-2. PMID 9795230.
• Rakhshandehroo M, Sanderson LM, Matilainen M, Stienstra R, Carlberg C, de Groot PJ, et al. (2007). "Comprehensive analysis of PPARalpha-dependent regulation of hepatic lipid metabolism by expression profiling". PPAR Res. 2007: 1–13. doi:10.1155/2007/26839. PMC 2233741. PMID 18288265.

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