PPAR-a

Current evidence suggests that PPAR activation may limit inflammation and hence atherosclerosis. Both PPAR-a and PPAR-y can reduce T-cell activation, as shown by decreased production of EFN-y. PPAR-a agonists also rqness endothelial VCAM-1 expression and inhibit the inflammatory activation of vascular SMCs, while PPAR-y agonists repress endothelial chemokine expression and decrease macrophage MMP production. 

A peroxisome proliferator-activated receptor (PPAR) binding site was identified in the murine FATP1 promoter. Several reports have shown a positive regulation of mouse FATPs by ligands that activate PPAR-a, PPAR-y, or PPAR-y/RXR heterodimers. 

Tissue-Specific Expression. In adult rodents, PPAR.a is expressed in liver, kidney, intestine, heart, skeletal muscle, retina, adrenal gland, and pancreas. In adult human, PPARa is expressed in the liver, heart, kidney, large intestine, skeletal muscle (mostly slow-twitch oxidative type I fibers), and in cells of atherosclerotic lesions (endothelial cells, smooth muscle cells, and monocytes/macrophages). Therefore, regardless of... 

Barish GD, Narkar VA, Evans RM (2006) PPARS a dagger in the heart of the metabolic syndrome. J Clin Invest 116 590-597... 

Fibrates work by reducing apolipoproteins B, C-III (an inhibitor of LPL), and E, and increasing apolipoproteins A-I and A-II through activation of peroxisome proliferator-activated receptors-alpha (PPAR-a), a nuclear receptor involved in cellular function. The changes in these apolipoproteins result in a reduction in triglyceride-rich lipoproteins (VLDL and IDL) and an increase in HDL. 

Omega-3 fatty acids (eicosapentaenoic acid and docosa-hexaenoic acid), the predominant fatty acids in the oil of cold-water fish, lower triglycerides by as much as 35% when taken in large amounts. Fish oil supplements may be useful for patients with high triglycerides despite diet, alcohol restriction, and fibrate therapy. This effect may be modulated thru PPAR-a and a reduction in apolipoprotein B-100 secretion. Omega-3 fatty acids reduce platelet aggregation and have... 

PPAR-a peroxisome proliferator-activated receptor-alpha... 

Netoglitazone is an insulin sensitizer currently in Phase II clinical trials. It is able to modulate both PPAR-a and PPAR-y subtypes of peroxisome proliferator-activated receptor (Phase ll). Metaglidasen (MBX-102) is the (—)-enantiomer of the NSAID halofenate. This selective PPAR-y nuclear receptor agonist is being evaluated (Phase II) as an insulin sensitizer. It is structurally different from the currently marketed glitazones (Figure 8.84). ... 

The 3,4-dihydro-22/-l,3-benzoxazin-4-one derivative DRF-2519 587, bearing a 2,4-thiazolidinedione moiety in the side chain attached to the nitrogen atom, proved to be an activator of the a- and y-types of the peroxisome proliferator-activated receptors (PPAR-a and -7), which endowed it with antidiabetic and hypolipidemic potential. Compound 587 demonstrated significant plasma glucose-, insulin-, and lipid-lowering activity in mice and improvement in lipid parameters in fat-fed rats <2006BMC584>. 

Lee, J., Richburg, J.H., Younkin, S.C. Boekelheide, K. (1997) The Fas system is a key regulator of germ cell apoptosis in the testes. Endocrinology, 128, 2081-2088 Lewis, D.F.V Lake, B.G. (1993) Interaction of some peroxisome prolrferators with the mouse liver peroxisome proliferator-activated receptor (PPAR) a molecular modelling and quantitative stracture-activity relationship (QSAR) study. Xenobiotica, 23, 79-96 Lewis, L.M., Flechtner, T.W., Kerkay, J., Pearson, K.H. Nakamoto, S. (1978) Bis(2-ethyl-hexyl) phthalate concentrations in the serum of hemodialysis patients. Clin. Chem., 24, 741-746... 

Peters, J.M., Cattley, R.C. Gonzalez, F.J. (1997a) Role of PPAR a in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14,643. 

Xu, X., Yana, K. X., Songa, H., and Loa, M. W. (2005a). Quantitative determination of a novel dual PPAR a/y agonist using on-line turbulent-flow extraction with liquid chromatography-tandem mass spectrometry. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 814 29-36. 

The fibrates are another class of antihyperlipidemic drug and are frequently coadministered with a statin. Fibrates act as agonists of the peroxisome proliferator-activated receptors (PPAR), particularly PPAR-a. PPARs are nuclear receptors that influence gene expression and lipid metabolism. Examples of fibrates include gemfibrozil (Lopid, A.110) and fenofibrate (Tricor, A.lll) (Figure A.30). Fenofibrate is hydrolyzed in the body to its active form, fenofibric acid (A.112). Fibrates do not decrease LDL levels as effectively as statins, but fibrates do elevate HDL cholesterol levels. 

Highly sensitive targeted lipidomic approaches are rapidly leading to the identification of new analogs of anandamide (Tan et al., 2006). The two major families of lipids that share common chemical structure with anandamide are FAEs and fatty acid amides. Although many of these lipids show no activity at CB receptors, they are known to bind and activate other receptors, such as transient receptor potential vanilloid type-1 (TRPV-1) and the nuclear receptor peroxisome proliferator-activated (PPAR-a). 

PPAR a receptor, gap junctional intercellular communication, and replicative DNA synthesis (Isenberg et al. 2000, 2001 Smith et al. 2000). Two major mechanisms have been proposed to account for peroxisome proliferator-induced hepatocarcinogenicity in rodents induction of sustained oxidative stress and enhanced cell proliferation and promotion. Suppression of hepatocellular apoptosis has also been suggested to play a role. 

Green S. 1995. PPAR a mediator of peroxisome proliferator action. Mutat Res 333 101-109. 

Ethinyl estradiol, buprenorphine ferulic acid, genistein naltrexone (low), naloxone (low), SN-38 (active metabolite of irinotecan) alizarin, quinalizarin, retigabine Bilirubin, chloropheno- Atazanavir, indinavir, xypropionic acid, chrysin, ketoconazole (AT, = 3 pM) clofibrate, 3-MC, oltipraz, phenylpropionic acid, phenobarbital, clotrimazole, rifampin, and St. John s wort. WY-14643 Response elements for AhR, CAR, GR, PPAR-a, PXR, Nrf2 (antioxidant response element) have been identified... 

Response elements for FXR and PPAR-a have been identified... 

In vivo induction experiments indicate response elements are present for CAR, PXR, and PPAR-a ligands... 

Vinyl A-(2-benzoylphenyl)-L tyrosine derivatives, (V), prepared by Jeppesen (5) were partial PPAR-a, PPAR-y, and PPAR-8 agonists and used in treating obesity, hyperglycemia, hyperlipidemia, and hypercholesterolemia. 

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