Peroxisome Proliferators Activate Extracellular Signal-regulated Kinases in Immortalized Mouse Liver Cells

Rokos, Carrie L.; Ledwith, Brian J.

doi:10.1074/jbc.272.20.13452

Cited by 73 publications

(33 citation statements)

References 38 publications

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“…In vitro assays as well as cellular studies implicate a strong cross-talk between kinase cascades and PPARs (17,19). Both PPAR␣ and PPAR␥ are phosphoproteins and MAPK, in particular Erk2, can modulate PPAR activity (59). Several consensus sites for PPAR␣ phosphorylation have been identified, and treatment of cells with PD98059 blocks PPAR␣ activity (60,61).…”

Section: Discussionmentioning

confidence: 99%

Ras/Mitogen-activated Protein Kinase (MAPK) Signaling Modulates Protein Stability and Cell Surface Expression of Scavenger Receptor SR-BI

Wood

Mulay

Darabi

et al. 2011

Journal of Biological Chemistry

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The mitogen-activated protein kinase (MAPK) Erk1/2 has been implicated to modulate the activity of nuclear receptors, including peroxisome proliferator activator receptors (PPARs) and liver X receptor, to alter the ability of cells to export cholesterol. Here, we investigated if the Ras-Raf-Mek-Erk1/2 signaling cascade could affect reverse cholesterol transport via modulation of scavenger receptor class BI (SR-BI) levels. We demonstrate that in Chinese hamster ovary (CHO) and human embryonic kidney (HEK293) cells, Mek1/2 inhibition reduces PPAR␣-inducible SR-BI protein expression and activity, as judged by reduced efflux onto high density lipoprotein (HDL). Ectopic expression of constitutively active H-Ras and Mek1 increases SR-BI protein levels, which correlates with elevated PPAR␣ Ser-21 phosphorylation and increased cholesterol efflux. In contrast, SR-BI levels are insensitive to Mek1/2 inhibitors in PPAR␣-depleted cells. Most strikingly, Mek1/2 inhibition promotes SR-BI degradation in SR-BI-overexpressing CHO cells and human HuH7 hepatocytes, which is associated with reduced uptake of radiolabeled and 1,1 -dioctadecyl-3,3,3 ,3 -tetramethylindocarbocyane-labeled HDL. Loss of Mek1/2 kinase activity reduces SR-BI expression in the presence of bafilomycin, an inhibitor of lysosomal degradation, indicating down-regulation of SR-BI via proteasomal pathways. In conclusion, Mek1/2 inhibition enhances the PPAR␣-dependent degradation of SR-BI in hepatocytes.Anti-atherosclerotic properties of HDL and the major HDL apolipoprotein, apoA-I, are believed to include their ability to induce signaling events that promote cholesterol export from peripheral cells to the liver for disposal. However, the signal transduction pathways that contribute to stimulate reverse cholesterol transport in macrophages and hepatocytes are not fully understood (1-3). HDL binding to receptors such as SR-BI 6 activates various cellular processes, including endothelial nitric-oxide synthase activation in endothelial cells (1-3) and proliferation in smooth muscle cells (4) but also cell surface localization of SR-BI in hepatocytes (5). Downstream targets of HDL include Src family kinases, phospholipase C and D, Ras, phosphatidylinositol 3-kinase (PI3K), Akt, the mitogen-activated protein kinase (MAPK) pathway (Mek1/2 and Erk1/2), and Rac/Rho GTPases (1-8). Other kinases implicated in HDL-or apoAI-inducible cholesterol transport include protein kinase C (PKC), protein kinase A (PKA), c-Jun N-terminal kinase (JNK), and p38 MAPK (9 -14).Alternatively, signaling pathways can modulate the activity of nuclear receptors, including PPAR and LXR, to alter the ability of cells to transport cholesterol (15-18). Indeed, post-translational phosphorylation via various kinases, including Erk1/2, can alter PPAR␣ and PPAR␣ co-activator activity in a liganddependent and -independent manner (17-25). Recent findings link Erk1/2 kinases with nuclear receptors and lipid export via ABCA1. First, enhanced Erk1/2 signaling increases ABCA1 expression and ABCA1-mediated phos...

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Section: Discussionmentioning

confidence: 99%

Ras/Mitogen-activated Protein Kinase (MAPK) Signaling Modulates Protein Stability and Cell Surface Expression of Scavenger Receptor SR-BI

Wood

Mulay

Darabi

et al. 2011

Journal of Biological Chemistry

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“…Previous studies have shown that PPARγ agonists can cause rapid MAPKs activation or Akt inhibition in multiple cell types [25,[39][40][41]], yet their interrelationship has not been fully addressed. We have demonstrated that, like many other non-natural ligands that transactivate EGFR signaling [42], TGZ can cause rapid, EGFRdependent transient Erk1/2 activation, which has an absolute requirement for Grb2 binding to EGFR.…”

Section: Discussionmentioning

confidence: 99%

Troglitazone inhibits cell proliferation by attenuation of epidermal growth factor receptor signaling independent of peroxisome proliferator-activated receptor γ

Yang

et al. 2009

Cell Res

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Peroxisome proliferator-activated receptors (PPAR) belong to the nuclear hormone receptor superfamily of ligand-dependent transcription factors. Recent results have shown that agonists of PPARγ, such as troglitazone (TGZ), can inhibit cell proliferation and promote cell differentiation independent of PPARγ. In the present study, we provide evidence that TGZ may bind directly to EGFR and trigger its signaling and internalization independent of PPARγ. Detailed studies revealed that prolonged incubation with TGZ effectively attenuated EGFR signaling by targeting the receptor to the endo-lysosomal degradation machinery. Although the extracellular signal-regulated kinasesignaling pathway was transiently activated by TGZ in EGFR overexpressing cancer cells, inhibition of EGF-induced Akt phosphorylation most likely accounted for the growth arrest of tumor cells caused by TGZ at pharmacologically achievable concentrations. Therefore, we have provided a new line of evidence indicating that TGZ inhibits cell proliferation by promoting EGFR degradation and attenuating Akt phosphorylation.

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

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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.

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Peroxisome Proliferators Activate Extracellular Signal-regulated Kinases in Immortalized Mouse Liver Cells

Cited by 73 publications

References 38 publications

Ras/Mitogen-activated Protein Kinase (MAPK) Signaling Modulates Protein Stability and Cell Surface Expression of Scavenger Receptor SR-BI

Ras/Mitogen-activated Protein Kinase (MAPK) Signaling Modulates Protein Stability and Cell Surface Expression of Scavenger Receptor SR-BI

Troglitazone inhibits cell proliferation by attenuation of epidermal growth factor receptor signaling independent of peroxisome proliferator-activated receptor γ

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

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