Disease relevance of PPARA

• Identification of the PPARA locus on chromosome 22q13.3 as a modifier gene in familial combined hyperlipidemia [1].
• Ongoing research indicates that modulation of PPAR activity might be an effective therapy for additional maladies associated with the metabolic syndrome, including obesity [2].
• More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, have proven effective in the treatment of dyslipidemia and diabetes [3].
• Here, we present the current state of knowledge regarding the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases [3].
• Activities of PPARs were assessed using JEG3 choriocarcinoma cells transfected with a PPAR-response element reporter construct (pTK-PPREx3-luc) and treated with PPAR ligands [4].

Psychiatry related information on PPARA

• Polymorphism in the peroxisome proliferator-activated receptor alpha gene influences the risk for Alzheimer's disease [5].
• Moreover, defense mechanisms provided by peroxisome proliferator-activated receptor alpha and omega fatty acid oxidation are readily overwhelmed, particularly in female rats and also in women who have low hepatic induction of fatty acid-binding protein (L-FABPc) [6].

High impact information on PPARA

• Here we report the crystal structure of a ternary complex containing the peroxisome proliferator-activated receptor-alpha ligand-binding domain bound to the antagonist GW6471 and a SMRT co-repressor motif [7].
• In contrast, PPAR-alpha and PPAR-gamma activators induce the expression of the gene encoding ABCA1, a transporter that controls apoAI-mediated cholesterol efflux from macrophages [8].
• PPAR-alpha and PPAR-gamma are both expressed in human macrophages where they exert anti-inflammatory effects [8].
• This prompted us to investigate the influence of different PPAR-activators on cholesterol metabolism and foam-cell formation of human primary and THP-1 macrophages [8].
• The activation of PPAR-alpha may promote foam-cell formation by inducing expression of the macrophage scavenger receptor CD36 [8].

Chemical compound and disease context of PPARA

• In contrast, PPAR-alpha or PPAR-gamma activation does not influence cholesterol efflux from macrophages isolated from patients with Tangier disease, which is due to a genetic defect in ABCA1 [8].
• Moreover, primary human liposarcoma cells can be induced to undergo terminal differentiation by treatment with the PPAR gamma ligand pioglitazone, suggesting that the differentiation block in these cells can be overcome by maximal activation of the PPAR pathway [9].
• These data suggest that apoptosis induced by sulindac sulfone is mediated, in part, by the COX-independent, PPAR-dependent transcriptional activation of SSAT, leading to reduced tissue polyamine contents in human colon cancer cells [10].
• Growing evidence points to a causative relationship between PPAR activity and the metabolic syndrome, including insulin resistance, glucose intolerance or type 2 diabetes, obesity, dyslipidemia, hypertension, atherosclerosis, and albuminuria [11].
• The peroxisome proliferator-activated receptor gamma specific agonists 15-deoxy-Delta12,14-prostaglandin J2, troglitazone, and rosiglitazone dose-dependently inhibited cell proliferation in four melanoma cell lines, whereas a specific agonist of peroxisome proliferator-activated receptor alpha had no such effect [12].

Biological context of PPARA

• In the acarbose group, subjects carrying the minor G allele of rs4253776 and the CC genotype of rs4253778 of PPARA had a 1.7- and 2.7-fold increased risk for diabetes [13].
• Single Nucleotide Polymorphisms of the Peroxisome Proliferator-Activated Receptor-{alpha} Gene (PPARA) Influence the Conversion From Impaired Glucose Tolerance to Type 2 Diabetes: The STOP-NIDDM Trial [13].
• The lack of a detrimental effect of the null phenotype in development and reproduction opens up the possibility for null or variant PPARalpha gene (PPARA) alleles in humans [14].
• No significant associations between PPARA haplotypes and the phenotypes or significant interactions between PPAR haplotypes and the occurrence of new clinical events were detected [15].
• It was shown that a common leucine to valine (L162V) substitution at the PPARalpha gene (PPARA) is functional and affects transactivation activity of PPARalpha ligands, such as PUFA, on a concentration-dependent basis [16].

Anatomical context of PPARA

• Here, we report for the first time that in two different human bladder cancer cell lines, RT4 (derived from grade I tumor) and T24 (derived from grade III tumor), VEGF (mRNA and protein) is differentially up-regulated by the three PPAR isotypes [17].
• PPAR activation also induces apoptosis in human monocyte-derived macrophages most likely through inhibition of nuclear factor-kappa B activity [18].
• The mRNA levels of PPAR gamma1, the predominant form in adipocytes, did not correlate with BMI, leptin mRNA levels, or fasting insulinemia in 29 subjects with various degrees of obesity [19].
• In skeletal muscle and heart, PPAR-alpha increases mitochondrial free fatty acid uptake and the resulting free fatty acid oxidation through stimulating the muscle-type carnitine palmitoyltransferase-I [18].
• PPARalpha (NR1C1) controls lipid oxidation and clearance in hepatocytes and PPARgamma (NR1C3) promotes preadipocyte differentiation and lipogenesis [20].

Associations of PPARA with chemical compounds

• CONCLUSION: These results indicate that elevated baseline TG levels and PPARA gene intron 7 G/G genotype were associated with TG reduction > 30% after fenofibrate treatment in patients with type 2 diabetes [21].
• This suggests that alterations in triglyceride-rich lipoprotein metabolism may be involved in the generation of the increase in LDL cholesterol observed with the L162V PPARA polymorphism [22].
• A single amino acid, which is tyrosine in PPAR alpha and histidine in PPAR gamma, imparts subtype selectivity for both thiazolidinedione and nonthiazolidinedione ligands [23].
• We report the x-ray crystal structure of the ligand binding domain of PPAR alpha (NR1C1) as a complex with the agonist ligand GW409544 and a coactivator motif from the steroid receptor coactivator 1 [23].
• This effect is potentiated by an RXR (retinoid-X-receptor), selective retinoid LG10068 providing support for a PPAR agonist-specific action on VEGF expression [17].

Physical interactions of PPARA

• All PPARs are, albeit to different extents, activated by fatty acids and derivatives; PPAR-alpha binds the hypolipidemic fibrates whereas antidiabetic glitazones are ligands for PPAR-gamma [18].
• Nuclear receptor corepressor (NCoR) was demonstrated to interact strongly with peroxisome proliferator-activated receptor alpha (PPARalpha), and PPARalpha ligands suppressed this interaction [24].
• Finally, NS 398, a COX-2 inhibitor, partially blocked the effect on PPAR activity and binding to the PPRE suggesting involvement of COX-2 metabolites in PPRE activation [25].
• These nucleotide substitutions prevent the binding of the retinoid X receptor alpha (RXR alpha)-peroxisome proliferator-activated receptor alpha (PPAR alpha) heterodimer without greatly altering the efficiency of binding of hepatocyte nuclear factor 4 (HNF4) to this recognition sequence [26].
• Methylation interference assays demonstrated that specific guanine residues required for RXR/PPAR binding to the ERE were similar to residues required for ER binding [27].
• Deletion studies indicated that PPARalpha interacted with NCoR receptor-interacting domain 1 (ID1) but not ID2 or ID3 [28].

Enzymatic interactions of PPARA

• Role for peroxisome proliferator-activated receptor alpha in oxidized phospholipid-induced synthesis of monocyte chemotactic protein-1 and interleukin-8 by endothelial cells [29].

Regulatory relationships of PPARA

• Transfection of peroxisome proliferator-activated receptor-alpha complementary DNA enhanced cytochrome P450 1A1 messenger RNA induction by WY-14643, although WY-14643 failed to activate xenobiotic responsive element sequences [30].
• We propose that hNUC1 represses the activity of hPPAR alpha by titrating out a factor required for activation [31].
• The present study explored the action of the PPAR alpha isoform and found that PPAR alpha agonists inhibited the A beta-stimulated expression of TNFalpha and IL-6 reporter genes in a dose-dependent manner [32].
• Human apical sodium-dependent bile salt transporter gene (SLC10A2) is regulated by the peroxisome proliferator-activated receptor alpha [33].
• Cells transfected with ERalpha deletion mutants demonstrate that the DNA binding domain of the ER is required to repress PPAR transactivation in these cells [34].

Other interactions of PPARA

• Evidence for a new human CYP1A1 regulation pathway involving PPAR-alpha and 2 PPRE sites [30].
• PPAR alpha and LXR alpha were mainly expressed in liver, while PPAR gamma1 predominated in adipose tissue and large intestine [19].
• Lipid infusion decreased PPARGC1A, PPARGC1B and PPARA expression to approximately 61, 77 and approximately 52% of basal values respectively, whereas expression of uncoupling protein 3 was upregulated 1.8-fold (all p<0.05) [35].
• PPARs consist of three families, PPAR-alpha, PPAR-delta and PPAR-gamma [36].
• Mutation analysis of the retinoid X receptor beta, nuclear-related receptor 1, and peroxisome proliferator-activated receptor alpha genes in schizophrenia and alcohol dependence: possible haplotype association of nuclear-related receptor 1 gene to alcohol dependence [37].

Analytical, diagnostic and therapeutic context of PPARA

• METHODS: We measured PPAR alpha, PPAR beta (delta) and PPAR gamma protein expression by western blot analysis [38].
• To evaluate whether PPAR-alpha and -delta subtypes are present in intrauterine tissues, placentae were obtained from women at term after spontaneous vaginal delivery (TSL; n = 15) and elective caesarean section before labor (TNL; n = 15) [4].
• Here we investigated the levels of PPAR alpha mRNA in primary cultures of human umbilical venous endothelial cells (HUVEC), human umbilical arterial endothelial cells (HUAEC), human coronary arterial endothelial cells (HCAEC), and human aortic endothelial cells (HAEC), using the reverse transcriptase-polymerase chain reaction (RT-PCR) [39].
• OBJECTIVE: Peroxisome proliferator-activated receptor (PPAR) ligands, widely used in type 2 diabetes treatment, have variably been shown to promote or prevent colon tumor formation in animal models and cell lines, but their role in normal human colon is unknown [40].
• PPAR ligands appear to be promising agents in limiting atherosclerosis; however, large-scale clinical trials are required to assess their safety and efficacy before they can be added to the clinicians' arsenal of antiatherosclerotic agents [41].

References