Phosphorylation of peroxisome proliferator-activated receptor α in rat Fao cells and stimulation by ciprofibrate

Passilly, Patricia; Schohn, Hervé; Jannin, Brigitte; Cherkaoui-Malki, Mustapha; Boscoboinik, Daniel; Dauça, Michel; Latruffe, Norbert

doi:10.1016/s0006-2952(99)00182-3

Cited by 38 publications

(26 citation statements)

References 37 publications

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“…Our results correlate with the work of Passilly et al (1999), who measured acyl-CoA oxidase activity as a marker gene for PPAR␣ in Fao cells. In their experiments, okadaic acid and vanadate treatment led to decreased acyl-CoA oxidase activity.…”

Section: Discussionsupporting

confidence: 90%

Modulation of Receptor Phosphorylation Contributes to Activation of Peroxisome Proliferator Activated Receptor α by Dehydroepiandrosterone and Other Peroxisome Proliferators

et al. 2007

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Dehydroepiandrosterone (DHEA), a C19 human adrenal steroid, activates peroxisome proliferator-activated receptor ␣ (PPAR␣) in vivo but does not ligand-activate PPAR␣ in transient transfection experiments. We demonstrate that DHEA regulates PPAR␣ action by altering both the levels and phosphorylation status of the receptor. Human hepatoma cells (HepG2) were transiently transfected with the expression plasmid encoding PPAR␣ and a plasmid containing two copies of fatty acyl coenzyme oxidase (FACO) peroxisome-proliferator activated receptor responsive element consensus oligonucleotide in a luciferase reporter gene. Nafenopin treatment increased reporter gene activity in this system, whereas DHEA treatment did not. Okadaic acid significantly decreased nafenopin-induced reporter activity in a concentration-dependent manner. Okadaic acid treatment of primary rat hepatocytes decreased both DHEA-and nafenopin-induced FACO activity in primary rat hepatocytes. DHEA induced both PPAR␣ mRNA and protein levels, as well as PP2A message in primary rat hepatocytes. Western blot analysis showed that the serines at positions 12 and 21 were rapidly dephosphorylated upon treatment with DHEA and nafenopin. Results using specific protein phosphatase inhibitors suggested that protein phosphatase 2A (PP2A) is responsible for DHEA action, and protein phosphatase 1 might be involved in nafenopin induction. Mutation of serines at position 6, 12, and 21 to an uncharged alanine residue significantly increased transcriptional activity, whereas mutation to negative charged aspartate residues (mimicking receptor phosphorylation) decreased transcriptional activity. DHEA action involves induction of PPAR␣ mRNA and protein levels as well as increased PPAR␣ transcriptional activity through decreasing receptor phosphorylation at serines in the AF1 region.

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Section: Discussionsupporting

confidence: 90%

Modulation of Receptor Phosphorylation Contributes to Activation of Peroxisome Proliferator Activated Receptor α by Dehydroepiandrosterone and Other Peroxisome Proliferators

et al. 2007

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“…This suggests that these compounds are not only agonists for PPARs but also influence PPAR transcriptional activity independent of receptor binding. In support of this, the PPAR␣ agonist ciprofibrate was previously shown to increase both EGFR (43) as well as PPAR␣ phosphorylation (62). Activation of PPAR␣ is required for the hypolipidemic and carcinogenic effects of peroxisome-proliferating PPAR␣ ligands (4,63).…”

Section: Discussionmentioning

confidence: 79%

Dependence of Peroxisome Proliferator-activated Receptor Ligand-induced Mitogen-activated Protein Kinase Signaling on Epidermal Growth Factor Receptor Transactivation

Gardner¹,

Dewar²,

Earp

et al. 2003

Journal of Biological Chemistry

101

108

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Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that function as ligandactivated transcription factors regulating lipid metabolism and homeostasis. In addition to their ability to regulate PPAR-mediated gene transcription, PPAR␣ and ␥ ligands have recently been shown to induce activation of mitogen-activated protein kinases (MAPKs), which in turn phosphorylate PPARs, thereby affecting transcriptional activity. However, the mechanism for PPAR liganddependent MAPK activation is unclear. In the current study, we demonstrate that various PPAR␣ (nafenopin) and ␥ (ciglitazone and troglitazone) agonists rapidly induced extracellular signal-regulated kinase (Erk) and/or p38 phosphorylation in rat liver epithelial cells (GN4). The selective epidermal growth factor receptor (EGFR) kinase inhibitors, PD153035 and ZD1839 (Iressa), abolished PPAR␣ and ␥ agonist-dependent Erk activation. Consistent with this, PPAR agonists increased tyrosine autophosphorylation of the EGFR as well as phosphorylation at a putative Src-specific site, Tyr 845 . Experiments with the Src inhibitor, PP2, and the antioxidant N-acetyl-L-cysteine revealed critical roles for Src and reactive oxygen species as upstream mediators of EGFR transactivation in response to PPAR ligands. Moreover, PPAR␣ and ␥ ligands increased Src autophosphorylation as well as kinase activity. EGFR phosphorylation, in turn, led to Ras-dependent Erk activation. In contrast, p38 activation by PPAR␣ and ␥ ligands occurred independently of Src, oxidative stress, the EGFR, and Ras. Interestingly, PPAR␣ and ␥ agonists caused rapid activation of proline-rich tyrosine kinase or Pyk2; Pyk2 as well as p38 phosphorylation was reduced by intracellular Ca 2؉ chelation without an observable effect on EGFR and Erk activation, suggesting a possible role for Pyk2 as an upstream activator of p38. In summary, PPAR␣ and ␥ ligands activate two distinct signaling cascades in GN4 cells leading to MAPK activation.

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“…5C). The phosphorylated protein is the more active form of this protein (44). Thus Marimastat increases not only expression but also activation of PPAR-␣, which may further facilitate ␤-oxidation of hepatic fat and reverse or prevent steatosis.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of matrix metalloproteinases increases PPAR-α and IL-6 and prevents dietary-induced hepatic steatosis and injury in a murine model

Alwayn

Andersson

Lee³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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Phosphorylation of peroxisome proliferator-activated receptor α in rat Fao cells and stimulation by ciprofibrate

Cited by 38 publications

References 37 publications

Modulation of Receptor Phosphorylation Contributes to Activation of Peroxisome Proliferator Activated Receptor α by Dehydroepiandrosterone and Other Peroxisome Proliferators

Modulation of Receptor Phosphorylation Contributes to Activation of Peroxisome Proliferator Activated Receptor α by Dehydroepiandrosterone and Other Peroxisome Proliferators

Dependence of Peroxisome Proliferator-activated Receptor Ligand-induced Mitogen-activated Protein Kinase Signaling on Epidermal Growth Factor Receptor Transactivation

Inhibition of matrix metalloproteinases increases PPAR-α and IL-6 and prevents dietary-induced hepatic steatosis and injury in a murine model

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