Chemistry:Pirinixic acid
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| Formula | C14H14ClN3O2S |
| Molar mass | 323.80 g·mol−1 |
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Pirinixic acid is a peroxisome proliferator-activated receptor alpha (PPARα) agonist that is under experimental investigation for prevention of severe cardiac dysfunction, cardiomyopathy and heart failure as a result of lipid accumulation within cardiac myocytes.[1] Treatment is primarily aimed at individuals with an adipose triglyceride lipase (ATGL) enzyme deficiency or mutation[1] because of the essential PPAR protein interactions with free fatty acid monomers derived from the ATGL catalyzed lipid oxidation reaction.[1] It was discovered as WY-14,643 in 1974.[2]
Adipose triglyceride lipase (ATGL)
Adipose triglyceride lipase (ATGL), an enzyme that catalyzes the rate limiting hydrolysis step of triglycerides[3] in the triacylglycerol lipolysis cascade, is expressed predominantly in adipose tissue, but is also found in lesser amounts within cardiac and skeletal muscle.[3] Its function is to initiate the breakdown of intracellular triglycerides into fatty acid monomers.[1] Individuals deficient in the ATGL enzyme are at higher risk for cardiac dysfunction and premature death because of increased size and accumulation of lipid droplets within cardiac myocytes.[4]
Peroxisome proliferator activated receptors (PPARs)
PPARs are a family of ligand activated receptors which include PPARα, PPARδ and PPARγ subtypes that are expressed in varying amounts in nuclear membranes of in different tissues.[5] PPAR activation occurs with free fatty acid binding, or fatty acid derivative ligands that have been broken down via the triacylglycerol lipolysis cascade.[1] Activated PPARs act as transcription factors to increase expression of specific genes within cells.[6] PPARα, a PPAR subtype, controls the expression of genes involved in cardiac fatty acid utilization,[6][7] and its activation, stimulates free fatty acid oxidation by increasing mitochondrial free fatty acid uptake and oxidation via two enzymes: carnitine palmitoyltransferase I (M-CPT I) and medium-chain acyl-CoA dehydrogenase (MCAD).[6]
Pre-clinical trials
ATGL deficient mice administered pirinixic acid demonstrated reduced cardiac hypertrophy and improved cardiac function.[1] These data demonstrate that genes induced by PPARα activation via free fatty acids from ATGL-dependent reactions are essential for the maintenance of normal cardiac function.[1] As PPARα activation triggers the expression of genes involved in lipid metabolism (M-CPTI I and MCAD),[6] treating the mice with pirinixic acid may improve cardiac myocyte energy supply by increasing mitochondrial fatty acid β-oxidation to prevent severe cardiac dysfunction as a result of lipid accumulation .
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Cardiac dysfunction in adipose triglyceride lipase deficiency: treatment with a PPARα agonist". British Journal of Pharmacology 165 (2): 380–9. January 2012. doi:10.1111/j.1476-5381.2011.01490.x. PMID 21585347.
- ↑ "A potent antihypercholesterolemic agent: (4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio) acetic acid (Wy-14643)". Experientia 30 (10): 1110–1. October 1974. doi:10.1007/BF01923636. PMID 4435102.
- ↑ 3.0 3.1 "Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase". Science 306 (5700): 1383–6. November 2004. doi:10.1126/science.1100747. PMID 15550674. Bibcode: 2004Sci...306.1383Z.
- ↑ "Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase". Science 312 (5774): 734–7. May 2006. doi:10.1126/science.1123965. PMID 16675698. Bibcode: 2006Sci...312..734H.
- ↑ "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. January 1996. doi:10.1210/endo.137.1.8536636. PMID 8536636.
- ↑ 6.0 6.1 6.2 6.3 "The role of the peroxisome proliferator-activated receptor alpha (PPAR alpha) in the control of cardiac lipid metabolism". Prostaglandins, Leukotrienes, and Essential Fatty Acids 60 (5–6): 339–43. 1999. doi:10.1016/s0952-3278(99)80009-x. PMID 10471118.
- ↑ "Peroxisome proliferator-activated receptor-alpha activators regulate genes governing lipoprotein metabolism, vascular inflammation and atherosclerosis". Current Opinion in Lipidology 10 (3): 245–57. June 1999. doi:10.1097/00041433-199906000-00007. PMID 10431661.
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