Kegg Pathway: PPAR signaling pathway

Cancer Res. 2008 Aug 15; 68(16): 6578-86
Zeng L, Geng Y, Tretiakova M, Yu X, Sicinski P, Kroll TG

Peroxisome proliferator-activated receptors (PPARs) are lipid-sensing nuclear receptors that have been implicated in multiple physiologic processes including cancer. Here, we determine that PPARdelta induces cell proliferation through a novel cyclin E1-dependent mechanism and is up-regulated in many human thyroid tumors. The expression of PPARdelta was induced coordinately with proliferation in primary human thyroid cells by the activation of serum, thyroid-stimulating hormone/cyclic AMP, or epidermal growth factor/mitogen-activated protein kinase mitogenic signaling pathways. Engineered overexpression of PPARdelta increased thyroid cell number, the incorporation of bromodeoxyuridine, and the phosphorylation of retinoblastoma protein by 40% to 45% in just 2 days, one usual cell population doubling. The synthetic PPARdelta agonist GW501516 augmented these PPARdelta proliferation effects in a dose-dependent manner. Overexpression of PPARdelta increased cyclin E1 protein by 9-fold, whereas knockdown of PPARdelta by small inhibitory RNA reduced both cyclin E1 protein and cell proliferation by 2-fold. Induction of proliferation by PPARdelta was abrogated by knockdown of cyclin E1 by small inhibitory RNA in primary thyroid cells and by knockout of cyclin E1 in mouse embryo fibroblasts, confirming a cyclin E1 dependence for this PPARdelta pathway. In addition, the mean expression of native PPARdelta was increased by 2-fold to 5-fold (P < 0.0001) and correlated with that of the in situ proliferation marker Ki67 (R = 0.8571; P = 0.02381) in six different classes of benign and malignant human thyroid tumors. Our experiments identify a PPARdelta mechanism that induces cell proliferation through cyclin E1 and is regulated by growth factor and lipid signals. The data argue for systematic investigation of PPARdelta antagonists as antineoplastic agents and implicate altered PPARdelta-cyclin E1 signaling in thyroid and other carcinomas.

Hepatology. 2008 Aug; 48(2): 458-73
Tomita K, Oike Y, Teratani T, Taguchi T, Noguchi M, Suzuki T, Mizutani A, Yokoyama H, Irie R, Sumimoto H, Takayanagi A, Miyashita K, Akao M, Tabata M, Tamiya G, Ohkura T, Hibi T

It is unclear how hepatic adiponectin resistance and sensitivity mediated by the adiponectin receptor, AdipoR2, contributes to the progression of nonalcoholic steatohepatitis (NASH). The aim of this study was to examine the roles of hepatic AdipoR2 in NASH, using an animal model. We fed C57BL/6 mice a methionine-deficient and choline-deficient (MCD) diet for up to 8 weeks and analyzed changes in liver pathology caused by either an AdipoR2 short hairpin RNA-expressing adenovirus or an AdipoR2-overexpressing adenovirus. Inhibition of hepatic AdipoR2 expression aggravated the pathological state of NASH at all stages: fatty changes, inflammation, and fibrosis. In contrast, enhancement of AdipoR2 expression in the liver improved NASH at every stage, from the early stage to the progression of fibrosis. Inhibition of AdipoR2 signaling in the liver diminished hepatic peroxisome proliferator activated receptor (PPAR)-alpha signaling, with decreased expression of acyl-CoA oxidase (ACO) and catalase, leading to an increase in lipid peroxidation. Hepatic AdipoR2 overexpression had the opposite effect. Reactive oxygen species (ROS) accumulation in liver increases hepatic production of transforming growth factor (TGF)-beta1 at all stages of NASH; adiponectin/AdipoR2 signaling ameliorated TGF-beta-induced ROS accumulation in primary cultured hepatocytes, by enhancing PPAR-alpha activity and catalase expression. CONCLUSION: The adiponectin resistance and sensitivity mediated by AdipoR2 in hepatocytes regulated steatohepatitis progression by changing PPAR-alpha activity and ROS accumulation, a process in which TGF-beta signaling is implicated. Thus, the liver AdipoR2 signaling pathway could be a promising target in treating NASH.

Mol Neurodegener. 2008; 3: 9
Inestrosa NC, Toledo EM

ABSTRACT: Recent evidence supports a neuroprotective role for Wnt signaling in neurodegenerative disorders such as Alzheimer's Disease (AD). In fact, a relationship between amyloid-beta-peptide (Abeta)-induced neurotoxicity and a decrease in the cytoplasmic levels of beta-catenin has been observed. APPARently Abeta binds to the extracellular cysteine-rich domain of the Frizzled receptor (Fz) inhibiting Wnt/beta-catenin signaling. Cross-talk with other signaling cascades that regulate Wnt/beta-catenin signaling, including the activation of M1 muscarinic receptor and PKC, the use of Ibuprofen-ChE bi-functional compounds, PPAR alpha, gamma agonists, nicotine and some antioxidants, results in neuroprotection against Abeta. These studies indicate that a sustained loss of Wnt signaling function may be involved in the Abeta-dependent neurodegeneration observed in Alzheimer's brain. In conclusion the activation of the Wnt signaling pathway could be proposed as a therapeutic target for the treatment of AD.

PPAR Res. 2008; 2008: 230893
Baranova A

Chemically synthesized ligands for nuclear receptors of the PPAR family modulate a number of physiological functions, particularly insulin resistance in the context of energy homeostasis and the metabolic syndrome. Additionally, these compounds may treat or prevent the development of many secondary consequences of the metabolic syndrome. Many PPAR agonists are also known to influence the proliferation and apoptosis of breast carcinoma cells though the experiments were carried out at suprapharmacological doses of PPAR ligands. It is possible that the breast epithelium of diabetics exposed to PPAR agonists will experience perturbation of the corresponding signaling pathway. Consequently, these patients' lifetime breast carcinoma risks could be modified, as their breast lesion incidence or the rates of the conversion of these lesions to carcinomas might vary upward or downward. PPAR activating treatment may also influence the progression of existing, undiagnosed invasive lesions. In this review, we attempt to summarize the possible influence of chemical PPAR ligands on the molecular pathways involved in the initiation and progression of breast carcinoma, with a major emphasis on PPARgamma agonists thiazolidinediones (TZDs).

J Biol Chem. 2008 Jul 18;
Quintanilla RA, Jin YN, Fuenzalida K, Bronfman M, Johnson GV

Peroxisome Proliferator-Activated Receptor- (PPAR) is a member of the PPAR family of transcription factors. Synthetic PPAR- agonists are used as oral anti-hyperglycemic drugs for the treatment of non-insulin-dependent diabetes mellitus. However, emerging evidence indicates that PPAR activators can also prevent or attenuate neurodegeneration. Given these previous findings, the focus of this paper is on the potential neuroprotective role of PPAR activation in preventing the loss of mitochondrial function in Huntington's Disease (HD). For these studies we used striatal cells that express wild type (STHdhQ7/Q7) or mutant (STHdhQ111/Q111) huntingtin protein at physiological levels. Treatment of mutant cells with thapsigargin resulted in a pronounced decrease in mitochondrial calcium uptake, an increase in reactive oxygen species (ROS) production, and a significant decrease in mitochondrial membrane potential. PPAR activation by rosiglitazone totally prevented the mitochondrial dysfunction and oxidative stress that occurred when mutant striatal cells were challenged with pathological increases in calcium. The beneficial effects of rosiglitazone were mediated by activation of the PPARgamma receptor, as all protective effects were prevented by the PPARgamma receptor antagonist GW9662. Additionally, the PPARgamma signaling pathway was significantly impaired in the mutant striatal cells with decreases in PPARgamma expression and reduced PPARgamma transcriptional activity. Treatment with rosiglitazone increased mitochondrial mass levels, suggesting a role for the PPARgamma pathway in mitochondrial function in striatal cells. Altogether, this evidence indicates that PPAR activation by rosiglitazone attenuates mitochondrial dysfunction in mutant huntingtin-expressing striatal cells, and this could be an important therapeutic avenue to ameliorate the mitochondrial dysfunction that occurs in HD.

Biochem Biophys Res Commun. 2008 Sep 19; 374(2): 231-6
Ghosh AK, Wei J, Wu M, Varga J

Transforming growth factor-beta (TGF-beta), a potent inducer of collagen synthesis, is implicated in pathological fibrosis. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a nuclear hormone receptor that regulates adipogenesis and numerous other biological processes. Here, we demonstrate that collagen gene expression was markedly elevated in mouse embryonic fibroblasts (MEFs) lacking PPAR-gamma compared to heterozygous control MEFs. Treatment with the PPAR-gamma ligand 15d-PGJ(2) failed to down-regulate collagen gene expression in PPAR-gamma null MEFs, whereas reconstitution of these cells with ectopic PPAR-gamma resulted in their normalization. Compared to control MEFs, PPAR-gamma null MEFs displayed elevated levels of the Type I TGF-beta receptor (TbetaRI), and secreted more TGF-beta1 into the media. Furthermore, PPAR-gamma null MEFs showed constitutive phosphorylation of cellular Smad2 and Smad3, even in the absence of exogenous TGF-beta, which was abrogated by the ALK5 inhibitor SB431542. Constitutive Smad2/3 phosphorylation in PPAR-gamma null MEFs was associated with Smad3 binding to its cognate DNA recognition sequences, and interaction with coactivator p300 previously implicated in TGF-beta responses. Taken together, these results indicate that loss of PPAR-gamma in MEFs is associated with upregulation of collagen synthesis, and activation of intracellular Smad signal transduction, due, at least in part, to autocrine TGF-beta stimulation.

Expert Opin Ther Targets. 2008 Aug; 12(8): 1049-63
Giaginis C, Spanopoulou E, Theocharis S

BACKGROUND: PPAR-gamma is a target for the treatment of metabolic disorders, as Pioglitazone and Rosiglitazone are already used against type 2 diabetes. Pleiotropic functions, such as antiproliferative and anti-inflammatory effects against several pathological states, including cardiovascular disease and cancer, are currently being explored in clinical studies. OBJECTIVE: Evidence indicates that PPAR-gamma is expressed in the placenta, playing a crucial role in placental development and function, while PPAR-gamma ligands appear to modulate fetal membrane signals. Thus, in the last few years, the pivotal role of