Peroxisome proliferator-activated receptor-alpha PPAR

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. 

The effect of dietary fats on hypertriglyceridemia is dependent on the disposition of double bonds in the fatty acids. Omega-3 fatty acids found in fish oils, but not those from plant sources, activate peroxisome proliferator-activated receptor-alpha (PPAR- ) and can induce profound reduction of triglycerides in some patients. They also have antiinflammatory and antiarrhythmic activities. In contrast, the omega-6 fatty acids present in vegetable oils may cause triglycerides to increase. 

Cuzzocrea, S., Di Paloa, R., Mazzon, E., Genovese, T., Muia, C., Centorrino, T., and Caputi, A. P. (2004). Role of endogenous and exogenous ligands for the peroxisome proliferators activated receptors alpha (PPAR-alpha) in the development of inflammatory bowel disease in mice. Lab. Invest. 84, 1643-1654. 

Murakami, K., Tobe, K., Ide, T., Mochizuki, T., Ohashi, M., Akanuma, Y., Yazaki, Y., and Kadowaki, T. (1998). A novel insulin sensitizer acts as a coligand for peroxisome proliferator-Activated Receptor-Alpha (PPAR-alpha) and PPAR-Gamma Effect of PPAR-Alpha Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats. Diabetes AT, 1841-1847. 

A. Mechanism and Effects Fibric acid derivatives (eg, gemfibrozil, fenofibrate, clofibrate) are ligands for the peroxisome proliferator-activated receptor-alpha (PPAR-a) protein, a receptor that regulates transcription of genes involved in lipid metabolism. Tbis interaction with PPAR-a results in increased activity of lipoprotein lipase and enhanced clearance of triglyceride-rich lipoproteins (Figure 35-2). Cholesterol biosynthesis in the liver is seeondarily reduced. The fibrates reduce serum triglyceride concentrations (Table 35-3). There may be a small reduction in LDL cholesterol and a small increase in HDL levels. 

Other endogenous fatty acid amides (such as palmitoylethanolamide, PEA) do not activate CBi and CB2 receptors, but they exhibit anti-inflammatory and analgesic properties [35], due to the interaction with peroxisome proliferator-activated receptor alpha (PPAR-a) and possibly also with the postulated new cannabinoid receptors GPR55 and GPR119 [36]. 

Onishchenko N, Fischer C, Ibrahim WNW et al (2011) Prenatal exposure to PFOS or PFOA alters motor function in mice in a sex-related manner. Neurotox Res 19(3) 452-461 Palkar PS, Anderson CR, Ferry CH et al (2010) Effect of prenatal peroxisome proliferator-activated receptor alpha (PPAR alpha) agonism on postnatal development. Toxicology 276(l) 79-84... 

Wolf CJ, Schmid JE, Lau C et al (2012) Activation of mouse and human peroxisome proliferator-activated receptor-alpha (PPAR alpha) by perfluoroalkyl acids (PFAAs) Further investigation of C4-C12 compounds. Reprod Toxicol 33(4) 546-551 Wolf CJ, Zehr RD, Schmid JE et al (2010) Developmental effects of perfluorononanoic acid in the mouse are dependent on peroxisome proliferator-activated receptor-alpha. PPAR Res 2010 1-11... 

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

PPAR- Peroxisome proliferator-activated receptor-alpha VLDL Very low density lipoproteins... 

Cristiano, F., Bernardo, A., and Ceru, M. P. (2001). Peroxisome proliferator-activated receptors (PPARs) and peroxisomes in rat cortical and cerebellar astrocytes. J. Neurocytol. 30, 671—683. Cullingford, T. E., Bhakoo, K., Peuchen, S., Dolphin, C. T., Patel, R., and Clark, J. B. (1998). Distribution of mRNAs encoding the peroxisome proliferator-activated receptor alpha, beta, and gamma and the retinoid X receptor alpha, beta, and gamma in rat central nervous system. J. Neurochem. 70, 1366-1375. 

Fig. 6. Coordinated transcriptional regulation of fatty acid desaturases and elongases in mammals. PUFA, polyunsaturated fatty acids +, stimulation inhibition LXR, liver X receptor RXR retinoid X receptor SREBP, sterol regulatory element binding protein ChREBP, carbohydrate response element binding protein Mix, Max-like receptor PPAR-ot, peroxisome proliferator activated receptor alpha LXRE, liver X receptor response element SRE, sterol response element ChoRE, carbohydrate response element PPRE, peroxisome proliferator response element. (See color plate section, plate no. 6.)...

PPAR-a Peroxisome proliferator-activated receptor-alpha one of a family of nuclear transcription regulators that participates in the regulation of metabolic processes... 

Braissant, O., Foufelle, F., Scotto, C., Dauca, M., and Wahli, W. (1996). Differential Expression of Peroxisome Proliferator-Activated Receptors (PPARs) Tissue Distribution of PPAR-Alpha, -Beta, and -Gamma in the Adult Rat. Endocrinology 137, 354—366. 

Yoshikawa T, Ide T, Shimano H, Yahagi N, Amemiya-Kudo M, Matsuzaka T, Yatoh S, Kitamine T, Okazaki H, Tamura Y, et al. Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. I. PPARs suppress sterol regulatory element binding protein-Ic promoter through inhibition of LXR signaling. Mol. Endocrinol. 2003 17 1240-1254. 

Michalik L, Desvergne B, Tan NS, et al. (2001) Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR)alpha and PPARbeta mutant mice. J Cell Biol 154 799-814... 

Kasuga, J., Yamasaki, D., Araya, Y, Nakagawa, A., Makishima, M., Doi, T., Hashimoto, Y, Miyachi, H. Design, synthesis, and evaluation of a novel series of alpha-substituted phenylpropanoic acid derivatives as human peroxisome proliferator-activated receptor (PPAR) alpha/ delta dual agonists for the treatment of metabolic syndrome. Bioorg. Med. Chem. 2006, 14, 8405-8414. 

Lawrence, J. W., li, Y, Chen, S., DeLuca, J. G., Berger, J. P, Umbenhauer, D. R., Moller, D. E., and Zhou, G. (2001a). Differential gene regulation in human versus rodent hepatocytes by peroxisome proliferator-activated receptor (PEAR) alpha. PPAR alpha fails to induce peroxisome proliferation-associated genes in human cells independently of the level of receptor expresson. J Biol Chem 276,... 

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