Peroxisome Proliferator-Activated Receptor β/δ (NR1C2)

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PPARs

The Peroxisome Proliferator-Activated Receptors (PPARs) are members of the nuclear receptor (NR) superfamily that have evolved to be the biological sensors of altered lipid metabolism, in particular that of intracellular fatty acid levels. An interesting and somewhat surprising finding is that these lipid sensors are also profound regulators of cell growth, differentiation and apoptosis in a wide variety of cells. The multifaceted responses of PPARs are mediated by three subtypes expressed in different tissues and at different times in development. The PPAR subfamily  (NR1C (1)) has been defined as PPARα (NR1C1), PPARβ (also called PPARδ and NUC1, NR1C2) and PPARγ (NR1C3), each with a possibility of different ligands, target genes and biological role. PPARs have been cloned in several species, including humans, rodents, amphibians, teleosts and cyclostoma (2). The expression of PPARα, β/δ and γ varies widely from tissue-to-tissue. In numerous cell types from either ectodermal, mesodermal, or endodermal origin, PPARs are coexpressed, although their concentration relative to each other varies widely (3).  PPARα is highly expressed in cells that have active fatty acid oxidation capacity including hepatocytes, cardiomyocytes, enterocytes, and the proximal tubule cells of kidney. PPARβ/δ is expressed ubiquitously and often at higher levels than PPARα and γ. PPARγ, expressed predominantly in adipose tissue and the immune system, exists as two distinct protein forms γ1 and γ2, which arise by differential transcription start sites and alternative splicing (4).

 

Role of PPARβ/δ in cancer

PPAR-β/δ / Bcl-6 and the Cell Cycle. PPARβ/δ is involved in inhibition of human keratinocyte proliferation by inhibiting G1 to S phase progression (5), inhibition of tumor endothelial cell proliferation in mice through modulation of the cell cycle regulatory gene p57(Kip2) (6), inhibition of epidermal cell proliferation through kinase regulation (7), attenuation of skin carcinogenesis by regulating  Ubiquitin C (8) and inhibition of colon carcinogenesis through PPARβ/δ-dependent induction of cathepsin E (9). Together, these studies indicate a clear role for the receptor as a regulator of cell proliferation in certain cell types. Another way that PPARβ/δ agonists may affect cell cycle regulation is through the known association of PPARβ/δ with the transcriptional repressor Bcl-6 (Figure 1) (10, 11). Ligand-activation of PPAR-β/δ induces a conformational change and subsequent release of Bcl-6, which is then free to repress inflammatory genes as well as cell cycle regulatory genes.  For example, Bcl-6 binds the promoter and suppresses transcription of the anti-apoptotic Bcl-XL gene (12) or the adhesion molecule VCAM (13).

 

PPARβ/δ/Bcl-6 and Inflammation

PPARβ/δ is a mediator of inflammation through its association with Bcl-6 as well as NF-kB (Figure 1).  The PPAR-β/δ / Bcl-6 complex is found associated with the PPAR response element (PPRE) in its unliganded state, along with various co-repressors.  Addition of ligand induces a conformational change and subsequent release of Bcl-6, which is then free to repress transcription of target genes, many of which are inflammatory mediators.  For example, in macrophages, addition of PPAR-β/δ-specific agonist GW-501516 decreased IL-1β, MCP-1 and MMP-9 protein levels, and this effect is attributed to release of Bcl-6 (10).  Furthermore, mice lacking Bcl-6 display increased Th2-type inflammation (14). In rat pancreatic beta cells, however, activation of PPARβ/δ does not regulate the inflammatory response, an observation that may be explained by the lack of Bcl-6 expression in these cells (15).

PPARβ/δ as a nutrient and metabolic sensor.

Fatty acids and their metabolites are known endogenous agonists of all PPARs, with PPARβ/δ exhibiting similar structural and geometric preference as PPARα, whereas PPARγ tends to prefer long-chain polyunsaturated fatty acids (16). PPARβ/δ agonists include linoleic acid, oleic acid, arachidonic acid and EPA, which has been co-crystallized within the ligand binding domain of this nuclear receptor (17).  Recently we have shown that ω-3 PUFAs and conjugated linoleic acid (CLA) are efficacious activators of PPARβ/δ, leading to a more pronounced level of activity than seen with PPARα, γ or retinoid-X-receptor-α (RXRα) (18). Prostaglandin A1 (PGA1), PGD2 and PGD1 can activate PPARβ/δ in reporter assays (19). Incubation of triglyceride rich lipoproteins with LPL results in the production of PPARβ ligands several molecules present in oxVLDL including 15-HETE, 13(S)-HODE and 4-HNE are agonists of PPARβ/δ (20). We have further examined the products of 13(S)-HODE, via the Hock Cleavage mechanism, which forms such alkenals as HpNE and HNE, to activate PPARβ/δ. In addition, modulating PPARβ/δ activity, either by activation with synthetic PPARβ/δ-selective agonist tetradecylthioacetic acid (TTA) or inhibition with PPAR pan-antagonist GW9662 (21), affects the sensitivity of hepatocytes to 4-HNE and other toxic agents.  Part of the protective effects of PPARβ/δ against toxic lipids and hydroperoxides is via regulation of detoxification enzymes such as aldehyde dehydrogenases and glutathione peroxidase (20).  This research raises the possibility that PPARβ/δ agonists may be utilized to prevent or treat diseases associated with the generation of reactive oxygen species (ROS). Support for this concept comes from examination of the PPARβ/δ null mouse which are more sensitive to a variety of hepatotoxicants (5).


References

1.            Committee NRN. A unified nomenclature system for the nuclear receptor superfamily. Cell 1999;97:161-3.

2.            Escher P, Wahli W. Peroxisome proliferator-activated receptors: insight into multiple cellular functions. Mutat Res 2000;448:121-38.

3.            Braissant O, Wahli W. Differential expression of peroxisome proliferator-activated receptor- alpha, -beta, and -gamma during rat embryonic development [In Process Citation]. Endocrinology 1998;139:2748-54.

4.            Fajas L, Auboeuf D, Raspe E, et al. The organization, promoter analysis, and expression of the human PPARgamma gene. J Biol Chem 1997;272:18779-89.

5.            Burdick AD, Bility MT, Girroir EE, et al. Ligand activation of peroxisome proliferator-activated receptor-beta/delta(PPARbeta/delta) inhibits cell growth of human N/TERT-1 keratinocytes. Cell Signal 2007;19:1163-71.

6.            Miller-Brusselbach S, Komhoff M, Reick M, et al. Deregulation of tumor angiogenesis and blockade of tumor growth in PPAR-b(-/-) mice. EMBO J 2007;26:3686-98.

7.            Kim DJ, Murray IA, Burns AM, Gonzalez FJ, Perdew GH, Peters JM. Peroxisome proliferator-activated receptor-beta/delta inhibits epidermal cell proliferation by down-regulation of kinase activity. J Biol Chem 2005;280:9519-27.

8.            Kim DJ, Akiyama TE, Harman FS, et al. Peroxisome proliferator-activated receptor beta (delta)-dependent regulation of ubiquitin C expression contributes to attenuation of skin carcinogenesis. J Biol Chem 2004;279:23719-27.

9.            Marin HE, Peraza MA, Billin AN, et al. Ligand activation of peroxisome proliferator-activated receptor beta inhibits colon carcinogenesis. Cancer Res 2006;66:4396-401.

10.            Lee CH, Chawla A, Urbiztondo N, Liao D, Boisvert WA, Evans RM. Transcriptional repression of atherogenic inflammation: Modulation by PPARd. Science 2003;302:453-7.

11.            Barish GD, Nakar VA, Evans RM. PPAR-b/d: A dagger in the heart of the metabolic syndrome. J Clin Invest 2006;116:590-7.

12.            Tang TT, Dowbenko D, Jackson A, et al. The Forkhead transcription factor AFX activates apoptosis by induction of the Bcl-6 transcriptional repressor. J Biol Chem 2002;277:14255-65.

13.            Mencarelli A, Renga B, Distrutti E, Fiorucci S. Antiatherosclerotic effect of farnesoid X receptor. Am J Physiol Heart Circ Physiol 2009;296:H272-81.

14.            Toney LM, Cattoretti G, Graf JA, et al. BCL-6 regulates chemokine gene transcription in macrophages. Nat Immunol 2000;1:214-20.

15.            Kharroubi I, Lee CH, Hekerman P, et al. BCL-6: a possible missing link for anti-inflammatory PPAR-delta signalling in pancreatic beta cells. Diabetologia 2006;49:2350-8.

16.            Willson TM, Brown PJ, Sternbach DD, Henke BR. The PPARs: from orphan receptors to drug discovery. J Med Chem 2000;43:527-50.

17.            Xu HE, Lambert MH, Montana VG, et al. Molecular recognition of fatty acids by peroxisome proliferator- activated receptors. Mol Cell 1999;3:397-403.

18.            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 PPAR{alpha}, {beta}, {gamma}, LXR{beta} and RXR{alpha}. Toxicol Sci 2006.

19.            Yu K, Bayona W, Kallen CB, et al. Differential activation of peroxisome proliferator-activated receptors by eicosanoids. J Biol Chem 1995;270:23975-83.

20.            Coleman JD, Prabhu KS, Thompson JT, et al. The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta). Free Radic Biol Med 2007;42:1155-64.

21.            Seimandi M, Lemaire G, Pillon A, et al. Differential responses of PPARalpha, PPARdelta, and PPARgamma reporter cell lines to selective PPAR synthetic ligands. Anal Biochem 2005;344:8-15.