Peroxisome proliferators activate growth regulatory pathways largely via peroxisome proliferator-activated receptor α-independent mechanisms

Pauley, Cindy J.; Ledwith, Brian J.; Kaplanski, Catherine

doi:10.1016/s0898-6568(01)00260-1

Cited by 33 publications

(26 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For instance, it has been reported that PPARa agonists rapidly induce MAP kinases activation (Rokos & Ledwith 1997, Gardner et al 2005b independently of PPARa (Gardner et al 2003). In addition, PPARa ligands have been found to induce expression of immediate early genes in cell lines that do not express this receptor (Pauley et al 2002). We have shown here that the PPARa agonist WY-14 643 modifies [Ca 2C ] i signals in islets from wild type as well as from Ppara gene disrupted mice.…”

Section: Discussionmentioning

confidence: 55%

“…In addition to this established mechanism of action, growing evidence points to the existence of a non-genomic effect of PPAR ligands via a PPARindependent pathway. These non-genomic actions include mitochondrial effects, rapid reactive oxygen species (ROS) formation, MAPK activation, and expression of immediate early genes, even in cell types that do not express PPAR (Pauley et al 2002, Gardner et al 2003, Perez-Ortiz et al 2004, Gardner et al 2005b. These actions are similar to those described for other nuclear receptors (Migliaccio et al 1998, Nadal et al 2001, Losel et al 2003.…”

Section: Introductionmentioning

confidence: 86%

See 1 more Smart Citation

Rapid non-genomic regulation of Ca2+ signals and insulin secretion by PPARα ligands in mouse pancreatic islets of Langerhans

Ropero

Juan-Picó²,

Rafacho³

et al. 2008

Journal of Endocrinology

View full text Add to dashboard Cite

PPARa is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. PPARa is involved in the regulation of in vivo triglyceride levels, presumably through its effects on fatty acid and lipoprotein metabolism. Some nuclear receptors have been involved in rapid effects mediated by non-genomic mechanisms. In this paper, we report the rapid non-genomic effects of PPARa ligands on the intracellular calcium concentration ([Ca 2C ] i ), mitochondrial function, reactive oxygen species (ROS) generation, and secretion of insulin in freshly isolated mouse islets of Langerhans. The hypolipidemic fibrate PPARa agonist WY-14 643 decreased the glucose-induced calcium oscillations in intact islets. This effect was mimicked by the synthetic agonist GW7647 and the endogenous agonist oleylethanolamide. The WY-14 643 action was rapid in onset (5 min) and was still produced in the presence of protein and mRNA synthesis inhibitors, cycloheximide, and actinomycin-D. This suggests that it is independent of gene transcription. In addition, WY-14 623 impaired mitochondrial function, increased ROS formation and decreased insulin release. PPARa is present in b-cells, mainly in the cytosol and nucleus, with a small subpopulation localized in the plasma membrane. However, the presence of the PPARa ligand effects in mice bearing a disrupted Ppara gene raises the possibility that the rapid effects of the agonists in pancreatic b-cells are independent of the receptor. We conclude that PPARa agonists produce a decrease in glucose-induced [Ca 2C ] i signals and insulin secretion in b-cells through a rapid, non-genomic mechanism.

show abstract

Section: Discussionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 86%

Rapid non-genomic regulation of Ca2+ signals and insulin secretion by PPARα ligands in mouse pancreatic islets of Langerhans

Ropero

Juan-Picó²,

Rafacho³

et al. 2008

Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…However, in these studies, changes in the phosphorylation status were detected shortly (10-30 minutes) after the treatment and therefore cannot be ascribed to canonical activity of PPARs as transcription factors. Such rapid, ''nongenomic'' effects are most likely PPAR independent (42,43). In our case, fenofibrate Akt, a cellular homologue of a retroviral oncoprotein v-Akt, is a kinase recruited during signal transduction from growth factor receptors and intracellular pathways.…”

Section: Discussionmentioning

confidence: 77%

Peroxisome Proliferator–Activated Receptor α Activation Decreases Metastatic Potential of Melanoma Cells In vitro via Down-Regulation of Akt

Grabacka

Płonka

Urbańska

et al. 2006

Clinical Cancer Research

139

147

View full text Add to dashboard Cite

Purpose: Peroxisome proliferator-activated receptors (PPAR) regulate lipid and glucose metabolism but their anticancer properties have been recently studied as well.We previously reported the antimetastatic activity of the PPARa ligand, fenofibrate, against melanoma tumors in vivo.Here we investigated possible molecular mechanisms of fenofibrate anti metastatic action. Experimental Design: Monolayer cultures of mouse (B16F10) and human (SkMell88) melanoma cell lines, soft agar assay, and cell migration assay were used in this study. In addition, we analyzed PPARa expression and its transcriptional activity in response to fenotibrate by using Western blots and liciferase-based reporter system. Results: Fenofibrate inhibited migration of B16F10 and SkMel188 cells in Transwell chambers and colony formation in soft agar.These effects were reversed by PPAR inhibitor, GW9662. Western blot analysis revealed time-dependent down-regulation of Akt and extracellular signal^regu-lated kinase l/2 phosphorylation in fenofibrate-treated cells. A B16F10 cell line stably expressing constitutively active Akt mutant was resistant to fenofibrate. In contrast, Akt gene silencing with siRNA mimicked the fenofibrate action and reduced the migratory ability of B16F1O cells. In addition, fenofibrate strongly sensitized BI6FIO cells to the proapoptotic drug staurosporine, further supporting the possibility that fenofibrate-induced down-regulation of Akt function contributes to fenofibrate-mediated inhibition of metastatic potential in this experimental model. Conclusions: Our results show that the PPAR-dependent antimetastatic activity of fenofibrate involves down-regulation of Akt phosphorylation and suggest that supplementation with this drug may improve the effectiveness of melanoma chemotherapy.

show abstract

“…Fenofibrate is a weak activator of PPAR␤/␦ and in other cell systems activates other pathways that are not PPAR dependent, such as non-receptor-mediated (nongenomic) effects. 42 There are other possible hypothesizes for an unfavorable outcome in fenofibrate-treated PO PPAR␣-deficient mice in addition to increasing fibrosis, mortality, and activating MMPs. These non-PPAR␣-mediated effects include proapoptosis by inhibiting Akt phosphorylation 43 and proapoptotic gene activation resulting in the progression to heart failure.…”

Section: Duhaney Et Al Fenofibrate Causes Adverse Myocardial Remodelingmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor α–Independent Actions of Fenofibrate Exacerbates Left Ventricular Dilation and Fibrosis in Chronic Pressure Overload

et al. 2007

View full text Add to dashboard Cite

Abstract-Progressive cardiac remodeling is characterized by subsequent chamber hypertrophy, enlargement, and pump dysfunction. It is also associated with increased cardiac fibrosis and matrix turnover. Interestingly, peroxisome proliferator-activated receptor (PPAR) ␣ activators reduce cardiac hypertrophy, inflammation, and fibrosis. Little is known about the role of fenofibrates in mediating PPAR␣-independent effects in response to chronic pressure overload (PO). Wild-type and PPAR␣-deficient mice were subjected to chronic PO caused by ascending aortic constriction to test the role of fenofibrates in chronic, progressive cardiac remodeling by a PPAR␣-independent mechanism. Mice were randomized to regular chow or chow-containing fenofibrate (100 mg/kg of body weight per day) for 1 week before and 8 weeks after ascending aortic constriction. In the presence of PPAR␣, wild-type chronic PO mice, treated with fenofibrate, had improved cardiac remodeling. However, PO PPAR␣-deficient mice treated with fenofibrate had increased mortality, significantly adverse left ventricular end diastolic (3.4Ϯ0.1 versus 4.2Ϯ0.1 mm) and end systolic (1.5Ϯ0.2 versus 2.5Ϯ0.2 mm) dimensions, and fractional shortening (57Ϯ3% versus 40Ϯ3%). Fenofibrate also increased myocardial hypertrophy, cardiac fibrosis, and the ratio of matrix metalloproteinase-2/tissue inhibitor of matrix metalloproteinase-2 in PO PPAR␣-deficient mice. Fenofibrate inhibited matrix metalloproteinase activity in vitro and aldosterone-induced increases in extracellular signal-regulated kinase phosphorylation. Thus, fenofibrate improved cardiac remodeling in chronic PO mice. However, in PPAR␣-deficient mice, this chronic PO was exacerbated and associated with increased myocardial fibrosis and altered matrix remodeling. In the absence of PPAR␣, fenofibrates exerts deleterious, pleiotropic myocardial actions. This is an important observation, because PPAR␣ agonists are considered possible inhibitory regulators of cardiac remodeling in the remodeled heart. (Hypertension. 2007; 49:1084-1094.)

show abstract

Peroxisome proliferators activate growth regulatory pathways largely via peroxisome proliferator-activated receptor α-independent mechanisms

Cited by 33 publications

References 20 publications

Rapid non-genomic regulation of Ca2+ signals and insulin secretion by PPARα ligands in mouse pancreatic islets of Langerhans

Rapid non-genomic regulation of Ca2+ signals and insulin secretion by PPARα ligands in mouse pancreatic islets of Langerhans

Peroxisome Proliferator–Activated Receptor α Activation Decreases Metastatic Potential of Melanoma Cells In vitro via Down-Regulation of Akt

Peroxisome Proliferator-Activated Receptor α–Independent Actions of Fenofibrate Exacerbates Left Ventricular Dilation and Fibrosis in Chronic Pressure Overload

Contact Info

Product

Resources

About