Influence of various fatty acids on the activity of protein phosphatase type 2C and apoptosis of endothelial cells and macrophages

Krieglstein, Josef; Hufnagel, B.; Dworak, Melanie; Schwarz, Stefanie; Kewitz, Tobias; Reinbold, Michael; Klumpp, Susanne

doi:10.1016/j.ejps.2008.08.007

Cited by 14 publications

(13 citation statements)

References 15 publications

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“…The phosphatase PPM1A, also known as protein phosphatase type 2C␣, was reported to directly dephosphorylate Smad2/3 and to be activated by unsaturated FA (33,34). We thus evaluated whether linoleic could target PPM1A to attenuate Smad-mediated signaling in gonadotrope cells using siRNA.…”

Section: Linoleic Targets the Phosphatase Ppm1a In L␤t2 Cellsmentioning

confidence: 98%

Unsaturated Fatty Acids Disrupt Smad Signaling in Gonadotrope Cells Leading to Inhibition of FSHβ Gene Expression

et al. 2014

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Reproductive function is highly dependent on nutritional input. We recently provided evidence that the unsaturated ω6 fatty acid (FA), linoleic acid (linoleic), interferes with transcription and secretion of the gonadotropin LH, highlighting the existence of a lipid sensing in pituitary gonadotropes. Here, we show, using a combination of in vivo and in vitro models, that linoleic differentially regulates Lhb and Fshb expression. Central exposure of rats to linoleic over 7 days was associated with increase of Lhb but not Fshb transcript levels. Consistently, exposure of rat pituitary cells or LβT2 cells to linoleic increased Lhb, whereas it dramatically decreased Fshb transcript levels without affecting its stability. This effect was also induced by ω9 and ω3-polyunsaturated FA but not by saturated palmitic acid. Analysis of the underlying mechanisms in LβT2 cells using small interfering RNA revealed that early growth response protein 1 mediates linoleic stimulation of Lhb expression. Furthermore, we demonstrated that linoleic counteracts activin and bone morphogenetic protein-2 stimulation of Fshb expression. Using Western blotting and Smad-responsive reporter gene assays, linoleic was shown to decrease basal Smad2/3 phosphorylation levels as well as activin- and bone morphogenetic protein-2-dependent activation of Smad, uncovering a new FA-sensitive signaling cascade. Finally, the protein phosphatase magnesium-dependent 1A was shown to mediate linoleic inhibition of basal Smad phosphorylation and Fshb expression, identifying protein phosphatase magnesium-dependent 1A as a new target of FA in gonadotropes. Altogether, this study provides a novel mechanism by which FAs target gene expression and underlines the relevant role of pituitary gonadotropes in mediating the effects of nutritional FA on reproductive function.

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Section: Linoleic Targets the Phosphatase Ppm1a In L␤t2 Cellsmentioning

confidence: 98%

Unsaturated Fatty Acids Disrupt Smad Signaling in Gonadotrope Cells Leading to Inhibition of FSHβ Gene Expression

et al. 2014

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“…Infusion of FFA also resulted in a 20% reduction in methacholine-induced, endothelium-dependent vasodilation in humans 20 , suggesting that plasma FFA may impair endothelial function 21 and might contribute to ischemic cardiomyopathy. Furthermore, FFA levels increase the activity of protein phosphatase type 2C, which causes apoptosis of endothelial cells 22,23 .…”

mentioning

confidence: 99%

Plasma Free Fatty Acids and Risk of Heart Failure

Djoussé

Benkeser

Arnold

et al. 2013

Circ: Heart Failure

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Background Although plasma free fatty acid (FFA) concentrations have been associated with lipotoxicity, apoptosis, and risk of diabetes and coronary heart disease, it is unclear whether FFA levels are associated with heart failure (HF). Methods and Results To test the hypothesis that plasma concentration of FFA is positively associated with incident HF, we prospectively analyzed data on 4248 men and women free of HF at baseline and aged 65+ years from the Cardiovascular Health Study. FFA concentration was measured in duplicate by the Wako enzymatic method. Incident HF was validated by a centralized Events Committee. We used Cox proportional hazards to estimate the hazard ratio of HF per standard deviation (SD) of FFA. During a median follow up of 10.5 y, 1,286 new cases of HF occurred. In a multivariable model adjusting for clinic site, comorbidity, demographic, anthropometric, and lifestyle factors, each SD (0.2 mEq/L) higher plasma FFA was associated with 12% (95% CI: 6% to 19%) higher risk of HF. Controlling for time-varying diabetes and coronary heart disease did not change the results [HR per SD: 1.16 (95% CI: 1.09–1.23)]. Conclusions A single measure of plasma FFA obtained later in life is associated with a higher risk of HF in older adults. Additional studies are needed to explore biologic mechanisms by which FFA may influence the risk of HF and determine whether FFA could serve as a novel pharmacological target for HF prevention.

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“…Hitherto PP2C isoforms have not been implicated in β-cell apoptosis. However, they are sensitive to stimulation by unsaturated fatty acids (Krieglstein, et al 2008). In this aspect PP2C isoforms have been linked to fatty acid-induced apoptosis in neural and endothelial cells (Schwarz, et al 2006) and similar mechanisms may be operative in pancreatic β-cells.…”

Section: Protein Phosphatases In β-Cell Proliferation and Apoptosismentioning

confidence: 99%

Protein phosphatases in pancreatic islets

Ortsäter¹,

Grankvist²,

Honkanen³

et al. 2014

Journal of Endocrinology

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The prevalence of diabetes is increasing rapidly world-wide. A cardinal feature of most forms of diabetes is the lack of insulin-producing capability, due to the loss of insulin-producing β-cells, impaired glucose-sensitive insulin secretion from the β-cell, or a combination thereof, the reasons for which largely remain elusive. Reversible phosphorylation is an important and versatile mechanism for regulating the biological activity of many intracellular proteins, which, in turn, controls a variety of cellular functions. For instance, significant changes in protein kinase activities and in protein phosphorylation patterns occur subsequent to stimulation of insulin release by glucose. Therefore, the molecular mechanisms regulating phosphorylation of proteins involved in the insulin secretory process by the β-cell have been extensively investigated. However, far less is known about the role and regulation of protein dephosphorylation by various protein phosphatases. Herein we review extant data implicating serine/threonine and tyrosine phosphatases in various aspects of healthy and diabetic islet biology, ranging from control of hormonal stimulus-secretion coupling to mitogenesis and apoptosis.

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Influence of various fatty acids on the activity of protein phosphatase type 2C and apoptosis of endothelial cells and macrophages

Cited by 14 publications

References 15 publications

Unsaturated Fatty Acids Disrupt Smad Signaling in Gonadotrope Cells Leading to Inhibition of FSHβ Gene Expression

Unsaturated Fatty Acids Disrupt Smad Signaling in Gonadotrope Cells Leading to Inhibition of FSHβ Gene Expression

Plasma Free Fatty Acids and Risk of Heart Failure

Protein phosphatases in pancreatic islets

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