PPAR-α is primarily activated through ligand binding. Endogenous ligands include fatty acids such asarachidonic acid as well as otherpolyunsaturated fatty acids and various fatty acid-derived compounds such as certain members of the15-hydroxyeicosatetraenoic acid family of arachidonic acid metabolites, e.g. 15(S)-HETE, 15(R)-HETE, and 15(S)-HpETE and13-hydroxyoctadecadienoic acid, alinoleic acid metabolite. Synthetic ligands include thefibrate drugs, which are used to treathyperlipidemia, and a diverse set of insecticides, herbicides, plasticizers, and organic solvents collectively referred to as peroxisome proliferators.
PPAR-α is atranscription factor regulated byfree 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 ofketogenesis, 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, andperoxisomal andmitochondrial fatty acidβ-oxidation.[10] Activation of fatty acid oxidation is facilitated by increased expression ofCPT1 (which brings long-chain lipids into mitochondria) by PPAR-α.[11] PPAR-α also inhibitsglycolysis, while promoting livergluconeogenesis andglycogen synthesis.[7]
Expression of PPAR-α is highest in tissues that oxidizefatty acids at a rapid rate. In rodents, highestmRNA 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.
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 ofketone bodies,hypoglycemia, andfatty liver.[8]
PPAR-α is the pharmaceutical target offibrates, a class of drugs used in the treatment of dyslipidemia. Fibrates effectively lower serumtriglycerides and raises serumHDL-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 ofcoronary heart disease, in contrast tostatins. PPAR-α, agonists may carry therapeutic value for the treatment ofnon-alcoholic fatty liver disease. PPAR-alpha may also be a site of action of certainanticonvulsants.[15][16]
An endogenous compound, 7(S)-Hydroxydocosahexaenoic Acid (7(S)-HDHA/"7-HDoHE".PubChem.National Center for Biotechnology Information.), which is aDocosanoid 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 hormoneFGF21 in humans by means of PPAR-α, although this effect can be accompanied by FGF21-resistance.[19]Amezalpat is an oral, small molecule, selective antagonist ofPPAR alpha being developed for treatment of hepatocellular carcinoma byTempest Therapeutics; it has gained orphan drug and fast track designation by theFDA.[citation needed]
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 includePDK4,ACOX1, andCPT1. 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 formouse liver andhuman liver, put PPAR-alpha at the center of a regulatory hub impacting fatty acid uptake and intracellular binding, mitochondrialβ-oxidation and peroxisomal fatty acid oxidation,ketogenesis, triglyceride turnover,gluconeogenesis, andbile synthesis/secretion.
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^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.PMID7684926.
^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.PMID18628776.S2CID23332777.
^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.PMID23206503.S2CID27701532.
^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.PMID32954732.S2CID221825661.
^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.PMID22107727.
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.PMID15497675.S2CID24728859.
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.PMID7981125.S2CID28301985.
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.PMID9795230.
