Heat Shock Protein-90 (Hsp90) Acts as a Repressor of Peroxisome Proliferator-Activated Receptor-α (PPARα) and PPARβ Activity

Sumanasekera, Wasana; Tien, Eric; Davis, John W.; Turpey, Rex; Perdew, Gary H.; Heuvel, John P. Vanden

doi:10.1021/bi0347353

Cited by 81 publications

(55 citation statements)

References 61 publications

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“…It is interesting that this promoter also contains, according to ConSite, responsive elements of c-fos and AP-2. The pSG5-mPPAR␣ and the pSG5-mPPAR␥ expression vector contains mouse PPAR␣ or mouse PPAR␥ and were kindly provided by Prof. G. Perdew (Penn State University, University Park, PA) and described in Sumanasekera et al (2003). The pcDNA3-PPAR␦ expression plasmid and the pcDNA3-PPAR␦E411P mutant cDNA of PPAR␦ were derived from pSG5-FAAR (Amri et al, 1995) as described in Bastie et al (2000).…”

Section: Methodsmentioning

confidence: 99%

Modulation of Peroxisome Proliferator-Activated Receptor δ Activity Affects Neural Cell Adhesion Molecule and Polysialyltransferase ST8SiaIV Induction by Teratogenic Valproic Acid Analogs in F9 Cell Differentiation

Lampen

Grimaldi²,

Nau³

2005

Molecular Pharmacology

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It has been suggested that the teratogenic effects of the antiepileptic drug valproic acid (VPA) is reflected in vitro by the differentiation of F9 cells, activation of peroxisome proliferatoractivated receptor ␦ (PPAR␦), and inhibition of histone deacetylases (HDACs). The aim of this study was to identify genes involved in the differentiation of F9 cells induced by VPA, teratogenic VPA derivatives, or the HDAC inhibitor trichostatin A (TSA) and to characterize the role of PPAR␦. Treatment of the cells with teratogenic VPA derivatives or TSA induced differentiation of F9 cells, mRNA, and protein expression of the neural cell adhesion molecule (NCAM) as well as activated the 5Ј-flanking region of the NCAM promoter, whereas nonteratogenic VPA derivatives had no effect at all. The polysialyltransferases [ST8SiaIV (PST1) and ST8SiaII] are responsible for the addition of polysialic acid (PSA) to NCAM. The mRNA expression of PST1 was highly induced by only teratogenic VPA derivatives and TSA. As shown by fluorescence-activated cell sorting analysis the level of PSA was higher after treatment of F9 cells with teratogenic VPA derivatives. It is interesting that overexpression of the PPAR␦ but not PPAR␣ or PPAR␥ in F9 cells resulted in higher induction of NCAM mRNA and protein expression and of PST1 mRNA expression (and a higher PSA level) than in mock-transfected F9 cells. Furthermore, repression of PPAR␦ activity in F9 cells inhibited these effects. We conclude that NCAM and PST1 are molecular markers in F9 cell differentiation caused by treatment with teratogenic VPA compounds or TSA and suggest that in addition to HDAC inhibition PPAR␦ is involved in the signaling pathway.

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Section: Methodsmentioning

confidence: 99%

Modulation of Peroxisome Proliferator-Activated Receptor δ Activity Affects Neural Cell Adhesion Molecule and Polysialyltransferase ST8SiaIV Induction by Teratogenic Valproic Acid Analogs in F9 Cell Differentiation

Lampen

Grimaldi²,

Nau³

2005

Molecular Pharmacology

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“…Like steroid receptors, PPARα interacts with hsp90 (6). The central DNAbinding domain (DBD) of PPARα is flanked by an N-terminal region called activating function-1 (AF-1) (7) that is activated by phosphorylation, as shown by insulin-stimulated AF-1 phosphorylation (S1).…”

Section: Structure Of Pparαmentioning

confidence: 99%

Sorting out the roles of PPAR in energy metabolism and vascular homeostasis

Lefèbvre

Chinetti-Gbaguidi²,

Fruchart³

et al. 2006

Journal of Clinical Investigation

835

645

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PPARα is a nuclear receptor that regulates liver and skeletal muscle lipid metabolism as well as glucose homeostasis. Acting as a molecular sensor of endogenous fatty acids (FAs) and their derivatives, this ligand-activated transcription factor regulates the expression of genes encoding enzymes and transport proteins controlling lipid homeostasis, thereby stimulating FA oxidation and improving lipoprotein metabolism. PPARα also exerts pleiotropic antiinflammatory and antiproliferative effects and prevents the proatherogenic effects of cholesterol accumulation in macrophages by stimulating cholesterol efflux. Cellular and animal models of PPARα help explain the clinical actions of fibrates, synthetic PPARα agonists used to treat dyslipidemia and reduce cardiovascular disease and its complications in patients with the metabolic syndrome. Although these preclinical studies cannot predict all of the effects of PPARα in humans, recent findings have revealed potential adverse effects of PPARα action, underlining the need for further study. This Review will focus on the mechanisms of action of PPARα in metabolic diseases and their associated vascular pathologies. IntroductionNutrient metabolism and energy homeostasis are tightly regulated by endocrine, paracrine, and autocrine signals that control the expression and activity of key metabolic enzymes and transport proteins by transcriptional and posttranscriptional mechanisms. Lipid mediators play a critical role in metabolic control, and the PPARs (NR1Cs), a class of ligand-activated transcription factors, have emerged as master transcriptional regulators of lipid and carbohydrate metabolism. Saturated and unsaturated long-chain fatty acids (FAs) and their eicosanoid derivatives are natural activators of this subclass of nuclear receptors. Increased recognition of a role for PPARs in metabolic regulation came following the discovery that the hypolipidemic fibrates and the insulin sensitizers thiazolidinediones were synthetic ligands for PPARα (NR1C1; refs. 1, 2) and PPARγ (NR1C3; ref. 3), respectively. PPARδ (NR1C3), also known as PPARβ, is the third PPAR isotype.Accumulating evidence supports a link between the 3 PPARs and diabetes, obesity, dyslipidemia, and inflammation. PPARα controls liver and skeletal muscle lipid metabolism, and glucose homeostasis. PPARα influences intracellular lipid and carbohydrate metabolism through direct transcriptional control of genes involved in peroxisomal and mitochondrial β-oxidation pathways, FA uptake, and triglyceride (TG) catabolism. Moreover, preclinical data suggest a role for PPARα in body weight control, supporting the use of PPARα agonists to treat obesity (4). Mice deficient in PPARα exhibit a delayed response to inflammatory stimuli (5). Several clinical trials demonstrate the efficiency of fibrates at decreasing circulatory inflammatory markers and reducing the progression of coronary atherosclerotic lesions. The ability of PPARα to improve

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“…Data were analyzed using a paired t test. know whether this occurs in EC, in hepatocytes it was shown that PPAR␣ associates with heat shock protein 90 and the cochaperone, hepatitis B virus X-associated protein 2 (XAP2) (34,35). Moreover, PPAR phosphorylation within the AF1 region of domain A/B via cytosolic MAPK has been reported to occur in response to environmental changes and extracellular signals (36).…”

Section: Expression Of Ppar␣ In Lcmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor-α Activation Inhibits Langerhans Cell Function

Dubrac

Stoitzner

Pirkebner

et al. 2007

The Journal of Immunology

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Epidermal Langerhans cells (LC) play a pivotal role in initiating and maintaining primary immune responses in the skin. In the present study, we asked whether peroxisome proliferator-activated receptor-α (PPARα) activation modulates LC function. Our results show that PPARα is expressed in immature LC and is down-regulated in mature LC suggesting that an early decrease of PPARα expression in LC may allow them to mature after contact with an Ag. We further show that pharmacologic PPARα activation inhibits LC maturation, migratory capacity, cytokine expression, and the ability to drive T cell proliferation. Moreover, PPARα activation inhibits NF-κB but not stress-activated protein kinase/JNK, p38MAPK, and ERK1/2. In conclusion, PPARα activation by endogenous ligands may provide a molecular signal that allows LC to remain in an immature state within the epidermis for extended periods of time despite minor environmental stimuli.

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Heat Shock Protein-90 (Hsp90) Acts as a Repressor of Peroxisome Proliferator-Activated Receptor-α (PPARα) and PPARβ Activity

Cited by 81 publications

References 61 publications

Modulation of Peroxisome Proliferator-Activated Receptor δ Activity Affects Neural Cell Adhesion Molecule and Polysialyltransferase ST8SiaIV Induction by Teratogenic Valproic Acid Analogs in F9 Cell Differentiation

Modulation of Peroxisome Proliferator-Activated Receptor δ Activity Affects Neural Cell Adhesion Molecule and Polysialyltransferase ST8SiaIV Induction by Teratogenic Valproic Acid Analogs in F9 Cell Differentiation

Sorting out the roles of PPAR in energy metabolism and vascular homeostasis

Peroxisome Proliferator-Activated Receptor-α Activation Inhibits Langerhans Cell Function

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