Peroxisome proliferator-activated receptor alpha

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.{{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 }} 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 hepato carcinogens that causes proliferation of peroxisomes.{{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 | bibcode = 1990Natur.347..645I | s2cid = 4306126 }}

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

File:PPARalpha transcriptome.png

File:Human hepatocyte PPARalpha transcriptome.png

PPAR-α is a transcription factor regulated by free fatty acids, and is a major regulator of lipid metabolism in the liver.{{cite journal | vauthors=Peeters A, Baes M | title=Role of PPARα in Hepatic Carbohydrate Metabolism | journal=PPAR Research | volume=2010 | pages=572405 | year=2010 | doi = 10.1155/2010/572405 | pmc=2948921 | pmid=20936117 | doi-access=free }} PPAR-alpha is activated under conditions of energy deprivation and is necessary for the process of ketogenesis, a key adaptive response to prolonged fasting.{{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 }}{{cite journal | vauthors=Grabacka M, Pierzchalska M, Dean M, Reiss K | title=Regulation of Ketone Body Metabolism and the Role of PPARα | journal=International Journal of Molecular Sciences | volume=17 | issue=12 | pages=E2093 | year=2016 | doi = 10.3390/ijms17122093 | pmc=5187893 | pmid=27983603| doi-access=free }} 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.{{cite journal | vauthors = Kersten S | title = Integrated physiology and systems biology of PPARα. | journal = Molecular Metabolism | volume = 3 | issue = 4 | pages = 354–371 | year = 2014 | pmid = 24944896 | pmc = 4060217 | doi = 10.1016/j.molmet.2014.02.002 }} Activation of fatty acid oxidation is facilitated by increased expression of CPT1 (which brings long-chain lipids into mitochondria) by PPAR-α.{{cite journal | vauthors=Rigamonti E, Chinetti-Gbaguidi G, Staels B| title=Regulation of macrophage functions by PPAR-alpha, PPAR-gamma, and LXRs in mice and men | journal=Arteriosclerosis, Thrombosis, and Vascular Biology | volume=28 | issue=6 | pages=1050–1059 | year=2008 | doi = 10.1161/ATVBAHA.107.158998 | pmid=18323516 | s2cid=26425698 }} PPAR-α also inhibits glycolysis, while promoting liver gluconeogenesis and glycogen synthesis.

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

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.{{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 | doi-access = free }} 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.{{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 | doi = 10.1128/MCB.15.6.3012 }} 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.

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.{{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 | s2cid = 23332777 }} 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.{{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 | bibcode = 2013PLoSO...864541P | doi-access = free }}{{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 | pages = 115–26 | year = 2013 | doi = 10.1016/j.neuropharm.2012.11.017 | pmid = 23206503 | s2cid = 27701532 }}

An endogenous compound, 7(S)-Hydroxydocosahexaenoic Acid (7(S)-HDHA/{{Cite PubChem|cid=131769809|title=7-HDoHE}}), 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.{{cite journal | vauthors = Liu J, Sahin C, Ahmad S, Magomedova L, Zhang M, Jia Z, Metherel AH, Orellana A, Poda G, Bazinet RP, Attisano L, Cummins CL, Peng H, Krause HM | title = The omega-3 hydroxy fatty acid 7(S)-HDHA is a high-affinity PPARα ligand that regulates brain neuronal morphology | journal = Science Signaling | volume = 15 | issue = 741 | pages = eabo1857 | date = July 2022 | pmid = 35857636 | doi = 10.1126/scisignal.abo1857 | doi-access = free }}

Previous evidence for the compound's function was speculative based on the structure and study of the chemical synthesis.{{cite journal |vauthors=Zhang M, Sayyad AA, Dhesi A, Orellana A |title=Enantioselective Synthesis of 7(S)-Hydroxydocosahexaenoic Acid, a Possible Endogenous Ligand for PPARα |journal=J Org Chem |volume=85 |issue=21 |pages=13621–13629 |date=November 2020 |pmid=32954732 |doi=10.1021/acs.joc.0c01770 |s2cid=221825661 |url=}}

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.{{cite journal | vauthors=Flippo KH, Potthoff MJ | title=Metabolic Messengers: FGF21 | journal=Nature Metabolism | volume=3 | issue=3 | pages=309–317 | year=2021 | doi = 10.1038/s42255-021-00354-2 | pmc=8620721 | pmid=33758421 }} Amezalpat is an oral, small molecule, selective antagonist of PPAR alpha being developed for treatment of hepatocellular carcinoma by Tempest Therapeutics; it has gained orphan drug and fast track designation by the FDA.{{fact|date=May 2025}}

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. 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,{{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 | doi-access = free }}
EP300
HSP90AA1,
NCOA1,{{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 | doi-access = free }}{{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 | doi-access = free }} and
NCOR1.{{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 | doi-access = free }}
Palmitoylethanolamide (PEA)
Oleoylethanolamide (OEA)
Anandamide (AEA)
7( S)-Hydroxydocosahexaenoic Acid (7-HDoHE)
PFAS{{cite journal | vauthors = Wolf CJ, Schmid JE, Lau C, Abbott BD | title = Activation of mouse and human peroxisome proliferator-activated receptor-alpha (PPARα) by perfluoroalkyl acids (PFAAs): further investigation of C4-C12 compounds | journal = Reproductive Toxicology | volume = 33 | issue = 4 | pages = 546–551 | date = July 2012 | pmid = 22107727 | doi = 10.1016/j.reprotox.2011.09.009 | bibcode = 2012RepTx..33..546W }}