Disease relevance of Ppara

• Adenoviral reconstitution of PPAR-alpha in the livers of nondiabetic, normotensive, dexamethasone-treated Ppara-/- mice induced hyperglycemia, hyperinsulinemia and increased gluconeogenic gene expression [1].
• Ppara+/+, but not Ppara-/-, mice developed hyperglycemia, hyperinsulinemia and hypertension [1].
• Neither hemizygous deletion of Pparg nor complete ablation of Ppara influenced the development of prostate cancer in our experimental context [2].
• We used a loss-of-function approach to investigate whether CLA ameliorated colitis through a peroxisome proliferator-activated receptor gamma (PPAR gamma)-dependent mechanism [3].
• In addition, this signalling pathway via PPREs is fully functional and can rescue the severe hypothermia phenotype observed in fasted PPARalpha-/- mice [4].
• We demonstrated that PPARalpha exerts a general control of the acute-phase response by using an inflammation/infection model of lipopolysaccharide [5].

Psychiatry related information on Ppara

• Our results, which show that OEA induces satiety by activating PPAR-alpha, identify an unexpected role for this nuclear receptor in regulating behaviour, and raise possibilities for the treatment of eating disorders [6].
• Treatment of alcohol-fed mice with a PPARalpha agonist reverses fatty liver despite continued alcohol consumption [7].

High impact information on Ppara

• In contrast to the well-established roles of PPARgamma and PPARalpha in lipid metabolism, little is known for PPARdelta in this process [8].
• By assaying arachidonate metabolites for their capacity to activate PPAR response elements, we have identified 15-deoxy-delta 12, 14-prostaglandin J2 as both a PPAR gamma ligand and an inducer of adipogenesis [9].
• PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3 [10].
• Human hepatocytes treated with dexamethasone and the PPAR-alpha agonist Wy14,643 induced PPARA and gluconeogenic gene expression [1].
• TRAP220 has been reported to show ligand-enhanced interaction with peroxisome proliferator-activated receptor gamma(2) (PPAR gamma(2)), a nuclear receptor essential for adipogenesis [11].

Chemical compound and disease context of Ppara

• In the present study, we assessed hyperlipidemia in Apc-deficient mice, model animals for human familial adenomatous polyposis, and examined the effects of pioglitazone and bezafibrate, respectively, PPARgamma and PPARalpha agonists, on both hyperlipidemia and intestinal polyposis [12].
• However, cotreatment with alcohol and LPS reduced both PPRE binding and nuclear levels of PPAR-alpha in fatty livers but increased those in lean livers [13].
• Impairment of PPARalpha function during ethanol consumption contributes to the development of alcoholic fatty liver, which can be overcome by Wy14,643 [14].
• Up-regulation of peroxisome proliferator-activated receptors (PPAR-alpha) and PPAR-gamma messenger ribonucleic acid expression in the liver in murine obesity: troglitazone induces expression of PPAR-gamma-responsive adipose tissue-specific genes in the liver of obese diabetic mice [15].
• Recently, we demonstrated that administration of the PPAR-alpha agonists gemfibrozil and fenofibrate, inhibit the clinical signs of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS) [16].

Biological context of Ppara

• Hepatic gluconeogenic gene expression was increased and insulin-mediated suppression of endogenous glucose production was less effective in dexamethasone-treated Ppara+/+ mice [1].
• Furthermore, Ppara-deficient mice exhibited sustained WAT inflammation during CL treatment, indicating that upregulation of Ppara limits proinflammatory signaling during chronic lipolytic activation [17].
• Histological, physiological, and molecular analysis of CL-induced remodeling in wild-type mice and mice lacking Ppara demonstrated that Ppara was important for inducing adipocyte mitochondrial biogenesis and upregulating genes involved in fatty acid oxidation [17].
• These results identify hepatic activation of PPAR-alpha as a mechanism underlying glucocorticoid-induced insulin resistance [1].
• Differential activation of adipogenesis by multiple PPAR isoforms [18].

Anatomical context of Ppara

• Ovulatory human chorionic gonadotropin downregulated expression of Pparg and Ppara in EMR1+ ovarian macrophages, but no hormonal responsiveness was observed in H2+ cells [19].
• Isolation of immune cells (EMR1+ or H2+) showed that Pparg and Ppara were expressed in ovarian macrophages at much higher levels than in peritoneal macrophages [19].
• Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma [20].
• We tested whether fasting-associated fatty acid release from adipose tissues alters hepatic transporter expression and bile formation in a PPARalpha-dependent manner [21].
• These data suggest that tissue-specific responsiveness to peroxisome proliferators, including certain fatty acids, is in part a consequence of differential expression of multiple, pharmacologically distinct PPAR isoforms [22].

Associations of Ppara with chemical compounds

• In contrast, the existence of an RXR/9-cis RA signalling pathway independent of PPAR or any other dimerization partner remains disputed [4].
• Surprisingly, PPAR gamma and -delta are not activated by pirinixic acid (Wy 14,643), a potent peroxisome proliferator and activator of PPAR alpha [22].
• Carnitine palmitoyl transferase-1 mRNA rose 52% in the wild-type mice but did not increase in PPAR alpha(-/-) mice [23].
• Despite similar degrees of hyperleptinemia and reduction in food intake, epididymal fat pad weight declined 55% in wild-type but only 6% in PPAR alpha(-/-) mice; liver triacylglycerol fell 39% in the wild-type group but was unchanged in PPAR(-/-) mice [23].
• Muc1 promoter is activated strongly and specifically by liganded PPARgamma but not PPARalpha or PPARdelta [24].
• Long-term treatment of these mice with clofibrate, a PPARalpha activator, induced HCC with mitochondrial abnormalities and hepatic steatosis [25].
• Glucose increased PPARalpha interaction with steroid receptor coactivator-1, DNA binding, and transactivation of beta-oxidation pathways in the presence of activating ligands [26].
• For the PPAR-alpha-null mouse, multivariate statistics highlighted hepatic steatosis, reductions in the concentrations of glucose and glycogen in both the liver and muscle tissue, and profound changes in lipid metabolism in each tissue, reflecting known expression targets of the PPAR-alpha receptor [27].

Physical interactions of Ppara

• A PPAR binding site (DR1) in the proximal Muc1 promoter acts as a basal silencer in the absence of PPARgamma, and its cooperation with a composite upstream enhancer element is both necessary and sufficient for PPARgamma-dependent induction of Muc1 [24].
• Electromobility shift assays showed that all three PPAR subtypes were able to bind specifically to the PPRE as heterodimers with RXRalpha [28].
• Responses of insulin-like growth factor (IGF)-I and IGF-binding proteins to nutritional status in peroxisome proliferator-activated receptor-alpha knockout mice [29].
• Gel shift assays demonstrated that LXR reduced binding of PPARalpha/retinoid X receptor (RXR) alpha to peroxisome proliferator response element [30].
• An intact DNA-binding domain is not required for peroxisome proliferator-activated receptor gamma (PPARgamma) binding and activation on some PPAR response elements [31].

Regulatory relationships of Ppara

• These results suggest that in the adult rodent heart, UCP-3 expression is regulated by PPARalpha [32].
• In conclusion, PPARalpha activation stimulates hepatic MTP expression via increased transcription of the Mtp gene [33].
• When challenged with a peroxisome proliferator, L-PBE-/- mice showed increases in the levels of hepatic mRNAs and proteins that are regulated by PPARalpha except for appreciable blunting of peroxisome proliferative response as compared with that observed in hepatocytes of wild type mice similarly treated [34].
• These results demonstrate that the FATP gene possesses a functional PPRE and is up-regulated by activators of PPARalpha and PPARgamma, thereby linking the activity of the protein to the expression of its gene [28].
• Under these conditions, hepatic PPAR gamma expression increased in both the control and PPAR alpha-deficient mice [35].

Other interactions of Ppara

• CONCLUSIONS: Induction of Mdr2 expression and function is part of the PPARalpha-mediated fasting response in mice [21].
• Reductions in the basal levels of apolipoprotein E (apoE) mRNA in macrophages and apoE protein in total plasma and high-density lipoprotein (HDL) were also observed in pIpC-treated PPAR gamma-MXCre(+) mice [36].
• In conclusion, PUFAs ameliorate obesity-associated symptoms, such as hepatic steatosis and insulin resistance, presumably through both down-regulation of SREBP-1 and activation of PPARalpha [37].
• Furthermore, both hyperglycemia and hyperinsulinemia in ob/ob mice were improved by PUFA administration, similar to the effect of PPARalpha activators [37].
• UCP-2, UCP-3, and PPARalpha expression were reduced when cardiac workload was either increased (pressure overload by aortic constriction) or decreased (mechanical unloading by heterotopic transplantation) [32].

Analytical, diagnostic and therapeutic context of Ppara

• The PPRE sequence specifically bound to the heterodimer of RXR alpha and PPAR alpha or PPAR gamma 2, as assessed by electrophoretic gel mobility shift assays [38].
• Furthermore, tissue-selective binding of PPAR alpha and PPAR gamma to the PPRE was demonstrated in hepatocytes and adipocytes, respectively, by chromatin immunoprecipitation assay [38].
• Matrix metalloproteinase (MMP) activity and intercellular adhesion molecule (ICAM)-1 in EE cells were measured in the presence and absence of Hcy, and ciprofibrate (CF; PPAR-alpha agonist) or 15-deoxy-Delta(12,14)-prostaglandin J(2) (PGJ(2); PPAR-gamma agonist) by zymography and Western blot analyses, respectively [39].
• Impaired Ras membrane association and activation in PPARalpha knockout mice after partial hepatectomy [40].
• Identification of novel peroxisome proliferator-activated receptor alpha (PPARalpha) target genes in mouse liver using cDNA microarray analysis [41].

References