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PPAR Activation (ppar + activation)

Distribution by Scientific Domains

Medical Sciences	50%

Selected Abstracts

PPAR gamma activators induce differentiation of B12 oligodendrocyte-like cells and rat spinal cord oligodendrocytes

JOURNAL OF NEUROCHEMISTRY, Issue 2002
A. D. Roth
The regulation of CNS lipid metabolism by nuclear receptors and their relation to cell differentiation remains undetermined. Since myelinating oligodendrocytes are the major lipid-synthesizing cells in the CNS, we characterized the effect of PPAR activation in a CNS derived cell line that expresses oligodendrocyte markers and compared these effects with oligodendrocyte primary cultures (90,95% pure). The rat glioma derived B12 cell line express the three major PPAR isoforms (PPAR ,, , and ,) and present a large number of peroxisomes, indicating an important lipid metabolism. Treatment with ciprofibrate, a general PPAR activator and clinical hypolipidemic, induces proliferation arrest, process extension and a moderate rise in the expression of acyl-CoA oxidase, a specific marker of peroxisomal proliferation. Cell growth arrest by ciprofibrate is enhanced 100-fold by low concentrations of retinoic acid (0.01 ,m), suggesting the involvement of the PPAR-retinoid acid receptor heterodimers. Since ciprofibrate possibly acts by modifying the concentration of endogenous PPAR ligands, we traced its effects to PPAR, by using isoform specific ligands: Troglitazone and 15-deoxy-prostaglandin J2, both of which induce growth arrest and process extension in B12 cells. These effects were corroborated on rat spinal cord derived oligodendrocytes primary cultures, where a significant rise in the number of mature oligodendrocytes is observed in response to PPAR, activators. These results show that PPAR,, a master gene in the differentiation of adipose tissue could be involved in the lipid metabolism of maturing oligodendrocytes. [source]

Novel Pirinixic Acids as PPAR, Preferential Dual PPAR,/, Agonists

MOLECULAR INFORMATICS, Issue 5 2009
Heiko Zettl
Abstract Pirinixic acid is a moderate agonist of both the alpha and the gamma subtype of the peroxisome proliferator activated receptor (PPAR). Previously, we have shown that ,-alkyl substitution leads to balanced low micromolar-active dual agonists of PPAR, and PPAR,. Taking ,-hexyl pirinixic acid as a new scaffold, we further optimized PPAR activity by enlargement of the lipophilic backbone by substituting the 2,3-dimethylphenyl with biphenylic moieties. Such a substitution pattern had only minor impact on PPAR, activity but further increased PPAR, activity leading to nanomolar activities. Supporting docking studies proposed that the (R)-enantiomer should fit the PPAR, ligand-binding pocket better and thus be more active than the (S)-enantiomer. Single enantiomers of selected active analogues were then prepared by enantio-selective synthesis and enantio-selective preparative HPLC, respectively. Biological data for the distinct enantiomers fully corroborated the docking experiments and substantiate a stereochemical impact on PPAR activation. [source]

Bisphenol A diglycidyl ether (BADGE) is a PPAR, agonist in an ECV304 cell line

BRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2000
David Bishop-Bailey
Peroxisome proliferator activated receptors (PPAR)s are nuclear transcription factors of the steroid receptor super-family. One member, PPAR,, a critical transcription factor in adipogenesis, is expressed in ECV304 cells, and when activated participates in the induction of cell death by apoptosis. Here we describe a clone of ECV304 cells, ECV-ACO.Luc, which stably expresses a reporter gene for PPAR activation. ECV-ACO.Luc respond to the PPAR, agonists, 15-deoxy-,12,14 PGJ2, and ciglitizone, by inducing luciferase expression. Furthermore, using ECV-ACO.Luc, we demonstrate that a newly described PPAR, antagonist, bisphenol A diglycidyl ether (BADGE) has agonist activities. Similar to 15-deoxy-,12,14 PGJ2, BADGE induces PPAR, activation, nuclear localization of the receptor, and induces cell death. British Journal of Pharmacology (2000) 131, 651,654; doi:10.1038/sj.bjp.0703628 [source]

Both the Peroxisome Proliferator-Activated Receptor , Agonist, GW0742, and Ezetimibe Promote Reverse Cholesterol Transport in Mice by Reducing Intestinal Reabsorption of HDL-Derived Cholesterol

CLINICAL AND TRANSLATIONAL SCIENCE, Issue 2 2009
François Briand Ph.D.
Abstract Peroxisome proliferator-activated receptor , (PPAR,) agonism increases HDL cholesterol and has therefore the potential to stimulate macrophage-to-feces reverse cholesterol transport (RCT). To test whether PPARÔ activation promotes RCT in mice, in vivo macrophage RCT was assessed using cholesterol-loaded/3H-cholesterol-labeled macrophages injected intraperitoneally. PPARÔ agonist GW0742 (10 mg/kg per day) did not change 3H-tracer plasma appearance, but increased fecal 3H-free sterols excretion by 103% (p < 0.005) over 48 hours. Total free cholesterol efflux from macrophages to serum (collected from both control and GW0742 groups) was not different, although ABCA1-mediated efflux was significantly higher with GW0742. The metabolic fate of HDL labeled with 3H-cholesteryl ether or 3H-cholesteryl oleate was also measured. While 3H-cholesteryl ether tissue uptake was unchanged, the 3H-tracer recovered in fecal free sterol fraction after 3H-cholesteryl oleate injection increased by 88% with GW0742 (p < 0.0005). This was associated with a lower Niemann-Pick C1 like 1 (NPC1L1) mRNA expression in the small intestine (p < 0.05). The same experiments in mice treated with ezetimibe, which blocks NPC1L1, showed a similar 2-fold increase in fecal free sterol excretion after labeled macrophages or HDL injection. In conclusion, PPARÔ activation enhances excretion of macrophage or HDL-derived cholesterol in feces through reduced NPC1L1 expression in mice, comparable to the effect of ezetimibe. [source]