Kegg Pathway: PPAR signaling pathway

KEGG ID: 03320

Reference Diagram

KEGG Diagram for PPAR signaling pathway

Rat

There are 68 IPI Records from this pathway found in Rattus norvegicus.

Location of PPAR signaling pathway proteins on Rat Genome

IPI Record Position
1: Acaa1 8:124305110-124313914
2: Acadl 9:65613130-65651775
3: Acadm 2:251866645-251890729
4: Acox1 10:106280444-106304660
5: Acox2 15:18647103-18677855
6: Acox3 14:80769000-80809809
7: Acsl1 16:49036892-49081416
8: Acsl3 9:78083235-78106933
9: Acsl4 X:36202358-36232162
10: Acsl5 1:261571863-261598237
11: Acsl6 10:39718739-39777776
12: Adipoq 11:79907786-79921124
13: Angptl4 7:16261621-16267852
14: Apoa1 :-
15: Apoa2 13:87114734-87116372
16: Apoa5 8:49253293-49255775
17: Apoc3 :-
18: Aqp7 5:58433731-58447853
19: Cd36 4:13472534-13522337
20: Cpt1a 1:205852746-205912969
21: Cpt1b 7:127737129-127746179
22: Cpt2 5:129007685-129025501
23: Cyp27a1 9:74039087-74068647
24: Cyp4a1 5:135901624-135915753
25: Cyp4a10 :-
26: Cyp4a3 5:135767919-135772855
27: Cyp4a8 :-
28: Cyp7a1 5:19707159-19716856
29: Cyp8b1 8:127018908-127020878
30: Dbi :-
31: Ehhadh 11:81474172-81507660
32: Fabp1 4:104412205-104415981
33: Fabp2 2:219591502-219605097
34: Fabp3 5:149340536-149347265
35: Fabp4 2:93536110-93540773
36: Fabp5 :-
37: Fabp6 10:28694773-28699448
38: Fabp7 20:36812599-36816205
39: Fads2 1:212512807-212542623
40: Gyk X:72421134-72493296
41: Hmgcs2 2:193128730-193143109
42: Ilk 1:163481299-163487550
43: Lpl 16:22532515-22556892
44: Me1 8:91841160-91955917
45: Mmp1a_predicted 8:4333815-4353725
46: Nr1h3 3:75542181-75552096
47: Oldlr1 4:166747228-166769340
48: Pck1 3:164012410-164018359
49: Pck2_predicted 15:33661629-33680492
50: Pdpk1 10:13329849-13362023
51: Plin 1:135497431-135509926
52: Pltp_predicted 3:155871842-155890270
53: Ppara 7:123729774-123807090
54: Ppard 20:6479092-6543024
55: Pparg 4:151492110-151617338
56: RGD1562373_predicted 8:124110412-124118925
57: Rxra 3:6666298-6689224
58: Rxrb 20:4954334-4960880
59: Rxrg 13:83256823-83298724
60: Scd1 1:249458699-249471514
61: Scd2 1:249358105-249371164
62: Scp2 :-
63: Slc27a1 16:18769909-18786990
64: Slc27a2 3:114073362-114113963
65: Slc27a4 3:8790158-8802884
66: Slc27a6_predicted 18:54351692-54411779
67: Ubc 12:32333187-32337945
68: Ucp1 19:26527548-26535621

Mouse

There are 68 IPI Records from this pathway found in Mus musculus.

Location of PPAR signaling pathway proteins on Mouse Genome

IPI Record Position
1: Acadl 1:66764061-66796457
2: Acadm 3:153859745-153881818
3: Acox1 11:115987978-116015135
4: Acox2 14:7019267-7052692
5: Acox3 5:35899921-35930662
6: Acsl1 8:47969859-48034867
7: Acsl3 1:78536898-78586015
8: Acsl4 X:137564361-137636903
9: Acsl5 19:55306619-55350970
10: Acsl6 11:54147221-54204962
11: Adipoq 16:23061870-23073302
12: Angptl4 17:33380630-33388455
13: Apoa1 9:45979952-45981463
14: Apoa2 1:173061764-173063045
15: Apoa5 9:46020073-46022914
16: Apoc3 9:45984046-45986292
17: Aqp7 4:41221917-41236641
18: Cd36 5:17297546-17340718
19: Cpt1a 19:3323320-3385732
20: Cpt1b 15:89244388-89253629
21: Cpt1c 7:44826526-44842856
22: Cpt2 4:107401912-107421466
23: Cyp27a1 1:74646781-74671097
24: Cyp4a10 4:115016219-115031581
25: Cyp4a12b 4:114796978-114936971
26: Cyp4a14 4:114984077-114994064
27: Cyp7a1 4:6192759-6202778
28: Cyp8b1 9:121763460-121764962
29: Dbi 1:121940826-121948625
30: Ehhadh 16:21675270-21701786
31: Fabp1 6:71129471-71134602
32: Fabp2 3:122887398-122891525
33: Fabp3 4:129811044-129817762
34: Fabp4 3:10186879-10191108
35: Fabp5 3:9995121-9999139
36: Fabp6 11:43439535-43444934
37: Fabp7 10:57473338-57476865
38: Fads2 19:10129825-10168474
39: Gk2 5:97695615-97697279
40: Gyk X:81958952-82029222
41: Hmgcs2 3:98365840-98396137
42: Ilk 7:105610473-105616745
43: IPI00378311 18:7581520-7581915
44: IPI00755916 5:125675482-125679691
45: Lpl 8:71809547-71836437
46: Me1 9:86378094-86492925
47: Mmp1a 9:7464141-7476856
48: Mmp1b 9:7368239-7387993
49: Nr1h3 2:90984949-90995955
50: Olr1 6:129453359-129472800
51: Pck1 2:172796012-172802209
52: Pck2 14:54494337-54504088
53: Pdpk1 17:23803292-23869207
54: Plin 7:79594677-79606283
55: Pltp 2:164530723-164548913
56: Ppara 15:85605326-85629024
57: Ppard 17:27960392-28029058
58: Pparg 6:115387685-115456020
59: Rxra 2:27499210-27585328
60: Rxrb 17:33642306-33648853
61: Rxrg 1:169435059-169476298
62: Scd1 19:44447766-44460864
63: Scd2 19:44347399-44360171
64: Scd3 19:44256599-44297327
65: Scp2 4:107541771-107616433
66: Slc27a1 8:74497916-74515697
67: Slc27a2 2:126244482-126279682
68: Slc27a4 2:29624689-29639531
69: Slc27a5 7:11888525-11898329
70: Slc27a6 18:58681609-58738238
71: Sorbs1 19:40348360-40451928
72: Ucp1 8:86180457-86188557

Human

There are 68 IPI Records from this pathway found in Homo sapiens.

Location of PPAR signaling pathway proteins on Human Genome

IPI Record Position
1: ACAA1 3:38139223-38153703
2: ACADL 2:210760963-210798405
3: ACADM 1:75962624-76001952
4: ACOX1 17:71453260-71487039
5: ACOX2 3:58465906-58497956
6: ACOX3 4:8419265-8493338
7: ACSL1 4:185913744-185984209
8: ACSL3 2:223433976-223516360
9: ACSL4 X:108771220-108863277
10: ACSL5 10:114123766-114178128
11: ACSL6 5:131170735-131375678
12: ADIPOQ 3:188043157-188058944
13: ANGPTL4 19:8335011-8345257
14: APOA1 11:116211677-116213876
15: APOA2 1:159458706-159460042
16: APOA5 11:116165293-116167821
17: APOC3 11:116205818-116208998
18: AQP7 9:33374948-33392517
19: CD36 7:80069459-80141668
20: CPT1A 11:68278666-68365960
21: CPT1B 22:49354156-49363862
22: CPT1C 19:54886219-54908800
23: CPT2 1:53434689-53626815
24: CYP27A1 2:219354745-219388254
25: CYP4A11 1:47167493-47180004
26: CYP4A22 1:47375433-47387940
27: CYP7A1 8:59565292-59575275
28: CYP8B1 3:42890807-42892312
29: DBI 2:119841055-119846586
30: EHHADH 3:186391108-186454531
31: FABP1 2:88203625-88208693
32: FABP2 4:120457854-120462766
33: FABP3 1:31610687-31618510
34: FABP4 8:82553484-82558023
35: FABP5 8:82355326-82359561
36: FABP6 5:159573319-159598307
37: FABP7 6:123142319-123146918
38: FADS2 11:61340325-61391401
39: GK X:30581397-30658646
40: GK2 4:80546717-80548378
41: HMGCS2 1:120092142-120113040
42: ILK 11:6581540-6588673
43: LOC387934 :-
44: LOC642956 :-
45: LPL 8:19841232-19867912
46: ME1 6:83976827-84197509
47: MMP1 11:102165861-102174099
48: NR1H3 11:47227083-47246972
49: OLR1 12:10202171-10216004
50: PCK1 20:55569543-55574922
51: PCK2 14:23633323-23643179
52: PDPK1 16:2527971-2593189
53: PLIN 15:88008607-88023595
54: PLTP 20:43960719-43974169
55: PPARA 22:44925163-45018317
56: PPARD 6:35418320-35503933
57: PPARG 3:12304359-12450840
58: RXRA 9:136358137-136472250
59: RXRB 6:33269343-33276417
60: RXRG 1:163636778-163681057
61: SCD 10:102096762-102114577
62: SCP2 1:53165536-53289870
63: SLC27A1 19:17442350-17477977
64: SLC27A2 15:48261716-48315873
65: SLC27A4 9:130142661-130163322
66: SLC27A5 19:63701516-63715244
67: SLC27A6 5:128328720-128396887
68: SORBS1 10:97061520-97311161
69: UBC 17:16225092-16226779
70: UCP1 4:141700500-141709457

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Recent Literature

Peroxisome proliferator-activated receptor-delta induces cell proliferation by a cyclin E1-dependent mechanism and is up-regulated in thyroid tumors.

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.

Hepatic AdipoR2 signaling plays a protective role against progression of nonalcoholic steatohepatitis in mice.

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.

The role of Wnt signaling in neuronal dysfunction in Alzheimer's Disease.

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 Ligands as Potential Modifiers of Breast Carcinoma Outcomes.

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).

Rosiglitazone treatment prevents mitochondrial dysfunction in mutant huntingtin expressing cells: Possible role of PPARgamma in the pathogenesis of huntington disease.

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.

Constitutive Smad signaling and Smad-dependent collagen gene expression in mouse embryonic fibroblasts lacking peroxisome proliferator-activated receptor-gamma.

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.

PPAR-gamma signaling pathway in placental development and function: a potential therapeutic target in the treatment of gestational diseases.

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