Introduction
Peroxisome Proliferator-Activated Receptor γ (PPARγ, PPARG, NR1C3) is expressed in many tissues including adipose, muscle, vascular cells, macrophages and epithelial cells of the mammary gland, prostate and colon (reviewed in [1]). Activated PPARγ induces LPL and fatty acid transporters (CD36), and enhances adipocyte differentiation, as well as inhibits cytokine and cylcooxygenase 2 (COX-2) expression, perhaps by modulating NFκB function (see Figure 1). The PPARγ null mouse is non-viable, implicating an important role for this protein in ontogeny [2], and also making the examination of a role for this receptor in gene expression difficult.
Clinically relevant anti-diabetic agents such as pioglitazone and rosiglitazone are potent PPARγ agonists (Kd in low nM range). A number of fatty acids and eicosanoid derivatives bind and activate PPARγ in the micromolar range [3]. Unlike the PPARα subtype, PPARγ has a clear preference for PUFAs [4]. The fatty acids LA, ALA, AA, and EPA bind PPARγ within the range of concentrations of free fatty acids found in human serum [5]. Although fatty acids are not particularly efficacious activators of PPARγ, intracellular conversion of fatty acids to eicosanoids, through enhanced expression of 15-lipoxygenase, greatly increased PPARγ mediated transactivation. [5]. Similar to PPARα, incubation of triglyceride rich lipoproteins with LPL results in the production of PPARγ ligands [6, 7]. In particular, oxidized LDL (OxLDL) products, 9-S-hydroxyoctadecadienoic acid (9-S-HODE), and 13-S-HODE are good PPARγ activators.
Role of PPARγ in Cardiovascular Disease.
The potential role of highly potent PPAR activators in the treatment of atherosclerosis has been noted by several investigators. Both PPARα and PPARγ play key roles in regulating fatty acid metabolism, albeit in seemingly opposite direction. The result of PPARα activation in rodent hepatocytes and certain other tissues is a dramatic increase in the peroxisomal enzymes with a modest increase in mitochondrial oxidation of fatty acids. In addition, lipid transport proteins such as FABP and acyl-CoA binding protein (ACBP) as well as genes involved in fatty acid and cholesterol export are under the control of PPARα. The targeted disruption of PPARα results in aberrant lipid metabolism with fat droplets accumulating in liver cells. Not only is peroxisomal metabolism affected, but also the constitutive levels of mitochondrial β-oxidation is less in the PPARα null mouse, showing the importance of this protein in overall fatty acid homeostasis.
The array of genes regulated by PPARγ in adipocytes is indicative of fatty acid accumulation. This regulation of gene expression is concomitant with increased differentiation of immature adipocytes into mature fat-storing cells [8]. These genes include LPL [9], adipocyte fatty acid binding protein (aP2) [10], and CD36 [11]. Adipocyte-secreted cytokines and hormones such as TNFα and leptin are also PPARγ target genes [12]. The genes regulated by PPARγ in macrophages are similar to those in the adipocyte and include LPL and CD36. Treatment of macrophages with PPARγ synthetic agonists inhibits the production of several cytokines such as interleukin 1-β and TNF-α and may result in an anti-inflammatory response [13]. Another link between PPARγ and inflammation is the fact that 15-deoxy PGJ2, a product of the cyclooxygenase pathway, and non-steroidal anti-inflammatory drugs (NSAIDS) are potent activators of PPARγ [14].
References
1. Spiegelman BM: PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 1998, 47(4):507-514.
2. Barak Y, Nelson MC, Ong ES, Jones YZ, Ruiz-Lozano P, Chien KR, Koder A, Evans RM: PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol Cell 1999, 4(4):585-595.
3. Krey G, Braissant O, F LH, Kalkhoven E, Perroud M, Parker MG, Wahli W: Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator- dependent receptor ligand assay. Mol Endocrinol 1997, 11(6):779-791.
4. Vanden Heuvel JP, Thompson JT, Frame SR, Gillies PJ: Differential activation of nuclear receptors by perfluorinated fatty acid analogs and natural fatty acids: a comparison of human, mouse, and rat peroxisome proliferator-activated receptor-alpha, -beta, and -gamma, liver X receptor-beta, and retinoid X receptor-alpha. Toxicol Sci 2006, 92(2):476-489.
5. Willson TM, Wahli W: Peroxisome proliferator-activated receptor agonists ]. Curr Opin Chem Biol 1997, 1(2):235-241.
6. Ziouzenkova O, Perrey S, Asatryan L, Hwang J, MacNaul KL, Moller DE, Rader DJ, Sevanian A, Zechner R, Hoefler G et al: Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: evidence for an antiinflammatory role for lipoprotein lipase. Proc Natl Acad Sci U S A 2003, 100(5):2730-2735.
7. Chawla A, Lee CH, Barak Y, He W, Rosenfeld J, Liao D, Han J, Kang H, Evans RM: PPARdelta is a very low-density lipoprotein sensor in macrophages. Proc Natl Acad Sci U S A 2003, 100(3):1268-1273.
8. Rocchi S, Auwerx J: Peroxisome proliferator-activated receptor-gamma: a versatile metabolic regulator. Ann Med 1999, 31(5):342-351.
9. Schoonjans K, Staels B, Auwerx J: The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta 1996, 1302(2):93-109.
10. Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM: mPpar gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev 1994, 8(10):1224-1234.
11. Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM: PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 1998, 93(2):241-252.
12. Zhang B, Berger J, Hu E, Szalkowski D, White-Carrington S, Spiegelman BM, Moller DE: Negative regulation of peroxisome proliferator-activated receptor-gamma gene expression contributes to the antiadipogenic effects of tumor necrosis factor-alpha. Mol Endocrinol 1996, 10(11):1457-1466.
13. Ricote M, Huang JT, Welch JS, Glass CK: The peroxisome proliferator-activated receptor(PPARgamma) as a regulator of monocyte/macrophage function. J Leukoc Biol 1999, 66(5):733-739.
14. Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA: Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem 1997, 272(6):3406-3410.
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