Disease relevance of Ppard

• Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity [1].
• In contrast to previous reports suggesting that activation of PPAR-delta potentiates colon polyp formation, here we show that PPAR-delta attenuates colon carcinogenesis [2].
• Peroxisome proliferator-activated receptor-delta (PPAR-delta; also known as PPAR-beta) is expressed at high levels in colon tumors, but its contribution to colon cancer is unclear [2].
• Conversely, wild-type mice that were given the specific PPARbeta/delta ligand L-165041 before renal ischemia were completely protected against renal dysfunction, as indicated by the lack of rise in serum creatinine and fractional excretion of Na+ [3].
• PPARbeta/delta, a very low-density lipoprotein sensor, is abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for approximately 40% of total body weight [4].

High impact information on Ppard

• As predicted, acute treatment of Lepr(db/db) mice with a PPARdelta agonist depletes lipid accumulation [1].
• In contrast to the well-established roles of PPARgamma and PPARalpha in lipid metabolism, little is known for PPARdelta in this process [1].
• In vitro, activation of PPARdelta in adipocytes and skeletal muscle cells promotes fatty acid oxidation and utilization [1].
• We show here that targeted activation of PPARdelta in adipose tissue specifically induces expression of genes required for fatty acid oxidation and energy dissipation, which in turn leads to improved lipid profiles and reduced adiposity [1].
• In both the Min mutant and chemically induced mouse models, colon polyp formation was significantly greater in mice nullizygous for PPAR-delta [2].

Chemical compound and disease context of Ppard

• Moreover, we surmise that PPARbeta/delta agonists would increase fatty acid catabolism, cholesterol efflux, and energy expenditure in muscle, and speculate selective activators of PPARbeta/delta may have therapeutic utility in the treatment of hyperlipidemia, atherosclerosis, and obesity [4].
• Prostaglandin E(2) promotes colorectal adenoma growth via transactivation of the nuclear peroxisome proliferator-activated receptor delta [5].
• Unexpectedly, gene array and functional analyses suggest that PPARdelta ameliorates hyperglycemia by increasing glucose flux through the pentose phosphate pathway and enhancing fatty acid synthesis [6].
• Moreover, the carbaprostacyclin-induced bone resorption was completely blocked by an antisense phosphothiorate oligodeoxynucleotide of PPARdelta/beta but not by the sense phosphothiorate oligodeoxynucleotide of the same DNA sequence [7].
• GlaxoSmithKline and Ligand are developing GW-501516, a peroxisome proliferator-activator receptor-delta agonist for the potential treatment of dyslipidemia [8].

Biological context of Ppard

• Localization of mouse peroxisome proliferator-activated receptor delta (Ppard) on chromosome 17 near colipase (Clps) [9].
• In this study, we defined the role of peroxisome proliferator-activated receptor beta/delta (PPARdelta) in metabolic homeostasis by using subtype selective agonists [10].
• These data suggest that PPARdelta is pivotal to control the program for fatty acid oxidation in the skeletal muscle, thereby ameliorating obesity and insulin resistance through its activation in obese animals [10].
• Similar PPARdelta-mediated gene activation was observed in the skeletal muscle of GW501516-treated mice [10].
• Increased caspase-3 activity associated with apoptosis was found in the skin of wild-type mice after tumor promotion with 12-O-tetradecanoylphorbol-13-acetate, and this effect was diminished in PPARbeta-null mice [11].

Anatomical context of Ppard

• Analysis of rat L6 myotubes treated with the PPARdelta subtype-selective agonist, GW501516, by the Affymetrix oligonucleotide microarrays revealed that PPARdelta controls fatty acid oxidation by regulating genes involved in fatty acid transport, beta-oxidation, and mitochondrial respiration [10].
• Inhibition of PKCalpha or COX-2 reduced cell proliferation in TPA-treated PPARbeta-null keratinocytes in a dose-dependent manner, whereas it only slightly influenced cell proliferation in wild-type keratinocytes [12].
• PPARalpha and PPARdelta activators did not up-regulate FATP expression in 3T3-L1 adipocytes, however, suggesting that these two subtypes do not play a significant role in differentiation-dependent activation in fat cells [13].
• On the basis of in vitro studies, PPARbeta/delta ligands seem to exert their role by activating the antiapoptotic Akt signaling pathway and, unexpectedly, by increasing the spreading of tubular epithelial cells, thus limiting potentially their shedding and anoikis [3].
• Therefore, whether PPARbeta/delta could contribute also to the control of tubular epithelium death after renal ischemia/reperfusion was tested [3].

Associations of Ppard with chemical compounds

• Furthermore, we show that treatment of muscle cells with GW501516 increases apolipoprotein-A1 specific efflux of intracellular cholesterol, thus identifying this tissue as an important target of PPARbeta/delta agonists [4].
• Furthermore, we show that the PPAR-dependent reporter in the muscle carnitine palmitoyl-transferase-1 promoter is directly regulated by PPARbeta/delta, and not PPARalpha in skeletal muscle cells in a PPARgamma coactivator-1-dependent manner [4].
• The murine UCP3 promoter is activated by fatty acids through either PPARalpha or PPARdelta but not by PPARgamma or retinoid X receptor alone [14].
• Finally, transient transfection assays established that endogenously synthesized prostacyclin (PGI(2)) could serve as a ligand for PPARdelta [15].
• In addition, the stable PGI(2) analog, carbaprostacyclin, and a synthetic PPARdelta agonist induced transactivation of endogenous PPARdelta in human colon carcinoma cells [15].
• A two-stage skin carcinogenicity bioassay was performed using wild-type and PPARbeta-null mice that were fed either a control diet or one containing 0.32 g sulindac/kg diet [16].

Physical interactions of Ppard

• This TGF-beta1/Smad3 action involves an inhibitory effect on AP-1 activity and DNA binding that results in an inhibition of the AP-1-driven induction of the PPARbeta/delta promoter [17].

Regulatory relationships of Ppard

• Our data suggest that PPARdelta is not directly regulated by beta-catenin, and that inhibition of PPARdelta activity is unlikely to be an appropriate strategy for the chemoprevention or chemotherapy of intestinal malignancies [18].
• Essential role of Smad3 in the inhibition of inflammation-induced PPARbeta/delta expression [17].
• In 3T3-L1 preadipocytes, simultaneous administration of a PPARdelta-selective ligand and MIX significantly enhanced the early expression of PPARgamma and ALBP/aP2, but only modestly promoted terminal differentiation as determined by lipid accumulation [19].
• The results reveal a dual role of TGF-beta1 as a chemoattractant of inflammatory cells and repressor of inflammation-induced PPARbeta/delta expression [20].
• Conversely, exposure of Rcho-1 cells to a PPARbeta/delta agonist triggers a massive differentiation via increased expression of 3-phosphoinositide-dependent kinase 1 and integrin-linked kinase and subsequent phosphorylation of Akt [21].
• Myocardial injury due to ischemia/reperfusion injury was significantly reduced in the MHC-PPARbeta/delta mice compared with control or MHC-PPARalpha mice, consistent with an increased capacity for myocardial glucose utilization [22].

Other interactions of Ppard

• Peroxisome proliferator-activated receptor beta (delta)-dependent regulation of ubiquitin C expression contributes to attenuation of skin carcinogenesis [11].
• PPAR-alpha is predominantly present in the liver, and PPAR-gamma in adipose tissue, whereas PPAR-delta is ubiquitously expressed [23].
• PPARdelta-dependent activation could be a potential compensatory mechanism to ensure appropriate expression of UCP3 gene in adult skeletal muscle in the absence of PPARalpha [14].
• The RXR-gamma gene was also down-regulated, but the RARalpha, beta, and gamma and PPARbeta and gamma genes were up-regulated [24].
• In these studies, the role of PPARbeta in modulating ubiquitin-dependent protein kinase Calpha (PKCalpha) levels and phosphorylation signaling pathways was evaluated [12].

Analytical, diagnostic and therapeutic context of Ppard

• The onset of tumor formation, tumor size, and tumor multiplicity induced from a two-stage carcinogen bioassay (7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate) were significantly enhanced in PPARbeta-null mice compared with wild-type mice [11].
• Real time quantitative PCR analyses showed that unlike in liver and heart, in mouse skeletal muscle PPAR delta is severalfold more abundant than either PPAR alpha or PPAR gamma [25].
• In situ hybridization studies demonstrate that PPARdelta is expressed in normal colon and localized to the epithelial cells at the very tips of the mucosal glands [15].
• We show that oral administration of the selective PPARdelta agonist GW0742 reduced clinical symptoms in C57BL/6 mice that had been immunized with encephalitogenic myelin oligodendrocyte glycoprotein (MOG) peptide [26].
• In addition, PPARalpha, PPARdelta/PPARbeta, and PPARgamma protein levels were analyzed by immunoblotting in normal epidermis and papillomas [27].

References