Peroxisome proliferator activated receptor interaction with genes

Kliewer, S. A., Sundseth, S. S., Jones, S. A., Brown, P J., Wisely, G. B., Koble, C. S., Devchand, P., Wahli, W., Willson, T. M., Lenhard, J. M., and Lehmann,J. M. (1997). Fatty Acids and Eicosanoids Regulate Gene Expression Through Direct Interactions with Peroxisome Proliferator-Activated Receptors Alpha and Gamma. Proc. Natl. Acad. Sci. U.S.A. 94, 4318-4323. 

Kliewer SA, et al. Patty acids and eicosanoids regulate gene ex- 93. pression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc. Natl. Acad. Sci. 

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. 

Moreover, studies about lipidogenesis and lipid metabolism have focused on a nuclear receptor, peroxisome proliferation-activated receptor y (PPAR-y). PPAR-y gene is a good example for involvement in a gene-environment interaction. Activation of PPAR-y leads to peroxisome proliferation and increased oxidation of fatty acids. PPAR-y activation results in adipocyte differentiation as well as improved insulin signaling of mature adipocytes. PPAR-y is associated with insulin resistance and blood pressure [5]. In individuals with a specific polymorphism in the PPAR-y (Prol2Ala), a low polyunsaturated-to-saturated fat ratio has been demonstrated to be associated with an increase in body mass index and fasting insulin concentrations [88]. 

Sugawara A, Uruno A, Kudo M, et al. Transcription suppression of thromboxane receptor gene by peroxisome proliferator-activated receptor-gamma via an interaction with Spl in vascular smooth muscle cells. J Biol Chem 2002 277 9676-9683. 

Vitamin A has a very important role in regulating the actions of other hormone- and nutrient-dependent genes because the RXRs can interact with other nuclear receptors to form heterodimers that are able to bind and regulate hormone and nutrient responsiveness. The RXRs are able to heterodimerize with the vitamin D receptor, the thyroid hormone receptors, the peroxisome proliferator activated... 

Fig. 5.2. Proposed mechanism of transcription activation by the peroxisome proliferator-activatedreceptor-y(PPARy). Upon binding to its ligand, the PPARy forms a heterodimeric complex with a retinoic acid receptor. This complex interacts then with peroxisome proliferator-responsive elements located in the promoter sequences of target genes.

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