The Peroxisome Proliferator-activated Receptor γ (PPARγ) Controls Natural Protective Mechanisms against Lipid Peroxidation in Amyotrophic Lateral Sclerosis

Benedusi, Valeria; Martorana, Francesca; Brambilla, Liliana; Maggi, Adriana; Rossi, Daniela

doi:10.1074/jbc.m112.366419

Cited by 52 publications

(38 citation statements)

References 70 publications

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“…Luciferase enzyme reporter assay on intestinal tissues was performed as described in previous study(25). Luciferase enzyme activity in the tissue extract was measured by the Luciferase system, according to the manufacturer’s instructions (Promega).…”

Section: Methodsmentioning

confidence: 99%

Homeostatic PPARα Signaling Limits Inflammatory Responses to Commensal Microbiota in the Intestine

Manoharan

Suryawanshi

Yuan

et al. 2016

The Journal of Immunology

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Dietary lipids and their metabolites activate members of the peroxisome proliferative-activated receptor (PPAR) family of transcription factors and are critical for colonic health. The PPARα isoform plays a vital role in regulating inflammation in various disease settings, but its role in intestinal inflammation, commensal homeostasis and mucosal immunity in the gut are unclear. Here, we demonstrate that the PPARα pathway in innate immune cells orchestrates gut mucosal immunity and commensal homeostasis by regulating the expression of IL-22 and the anti-microbial peptides RegIIIβ, RegIIIγ and calprotectin. In addition, the PPARα pathway is critical for imparting regulatory phenotype in intestinal macrophages. PPARα deficiency in mice resulted in commensal dysbiosis in the gut resulting in microbiota-dependent increase in the expression of inflammatory cytokines and enhanced susceptibility to intestinal inflammation. Pharmacological activation of this pathway decreased the expression of inflammatory cytokines and ameliorated colonic inflammation. Together, these findings identify a new important innate immune function for the PPARα signaling pathway in regulating intestinal inflammation, mucosal immunity and commensal homeostasis. Thus, the manipulation of the PPARα pathway could provide novel opportunities for enhancing mucosal immunity and treating intestinal inflammation.

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Section: Methodsmentioning

confidence: 99%

Homeostatic PPARα Signaling Limits Inflammatory Responses to Commensal Microbiota in the Intestine

Manoharan

Suryawanshi

Yuan

et al. 2016

The Journal of Immunology

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“…Gene and protein concentrations of PPAR-g, an FA-sensitive nuclear transcription factor that regulates lipid esterification and storage (41,42), were lower in the placentas of women with a high n-3:n-6 ratio (low n-6 FAs). Metabolites of the n-6 fatty acid arachidonate stimulate PPAR-g in the placenta and other tissues (43,44), suggesting that low n-6 may contribute to these effects. Although FAS expression was negatively correlated with maternal n-3 enrichment, FAS activity is very modest in the human placenta (45).…”

Section: Discussionmentioning

confidence: 99%

Effect of ω-3 supplementation on placental lipid metabolism in overweight and obese women

Calabuig-Navarro

Puchowicz

Glazebrook

et al. 2016

The American Journal of Clinical Nutrition

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Background: The placentas of obese women accumulate lipids that may alter fetal lipid exposure. The long-chain omega-3 fatty acids (n-3 FAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) alter FA metabolism in hepatocytes, although their effect on the placenta is poorly understood. Objective: We aimed to investigate whether n-3 supplementation during pregnancy affects lipid metabolism in the placentas of overweight and obese women at term. Design: A secondary analysis of a double-blind randomized controlled trial was conducted in healthy overweight and obese pregnant women who were randomly assigned to DHA plus EPA (2 g/d) or placebo twice a day from early pregnancy to term. Placental FA uptake, esterification, and oxidation pathways were studied by measuring the expression of key genes in the placental tissue of women supplemented with placebo and n-3 and in vitro in isolated trophoblast cells in response to DHA and EPA treatment. Results: Total lipid content was significantly lower in the placentas of overweight and obese women supplemented with n-3 FAs than in those supplemented with placebo (14.14 6 1.03 compared with 19.63 6 1.45 mg lipid/g tissue; P , 0.05). The messenger RNA expression of placental FA synthase (FAS) and diacylglycerol O-acyltransferase 1 (DGAT1) was negatively correlated with maternal plasma enrichment in DHA and EPA (P , 0.05). The expression of placental peroxisome proliferator-activated receptor g (r = 20.39, P = 0.04) and its target genes DGAT1 (r = 20.37, P = 0.02) and PLIN2 (r = 20.38, P = 0.04) significantly decreased, with an increasing maternal n-3: n-6 ratio (representing the n-3 status) near the end of pregnancy. The expression of genes that regulate FA oxidation or uptake was not changed. Birth weight and length were significantly higher in the offspring of n-3-supplemented women than in those in the placebo group (P , 0.05), but no differences in the ponderal index were observed. Supplementation of n-3 significantly decreased FA esterification in isolated trophoblasts without affecting FA oxidation. Conclusion: Supplementing overweight and obese women with n-3 FAs during pregnancy inhibited the ability of the placenta to esterify and store lipids. This trial was registered at clinicaltrials.gov as NCT00957476.Am J Clin Nutr 2016;103:1064-72.

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“…Thus, it remains unclear if PPARy agonists generally enhance peroxisome abundance or specifically alter the expression of selected peroxisomal genes. Since PPAR-γ agonists have been considered as potential therapeutic agents for a wide range of neurological diseases, including neurodegenerative and demyelinating diseases [7,87,97,155], it is a prerequisite to closely examine the proteomic alterations induced in peroxisomes in response to the drugs in order to avoid negative side effects by potentially impeding individual metabolic functions in the organelle.…”

Section: Other Ppar Family Membersmentioning

confidence: 99%

Proliferation and fission of peroxisomes — An update

Schrader

Costello

Godinho

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

124

142

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In mammals, peroxisomes perform crucial functions in cellular metabolism, signalling and viral defense which are essential to the health and viability of the organism. In order to achieve this functional versatility peroxisomes dynamically respond to molecular cues triggered by changes in the cellular environment. Such changes elicit a corresponding response in peroxisomes, which manifests itself as a change in peroxisome number, altered enzyme levels and adaptations to the peroxisomal structure. In mammals the generation of new peroxisomes is a complex process which has clear analogies to mitochondria, with both sharing the same division machinery and undergoing a similar division process. How the regulation of this division process is integrated into the cell's response to different stimuli, the signalling pathways and factors involved, remains somewhat unclear. Here, we discuss the mechanism of peroxisomal fission, the contributions of the various division factors and examine the potential impact of post-translational modifications, such as phosphorylation, on the proliferation process. We also summarize the signalling process and highlight the most recent data linking signalling pathways with peroxisome proliferation.

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The Peroxisome Proliferator-activated Receptor γ (PPARγ) Controls Natural Protective Mechanisms against Lipid Peroxidation in Amyotrophic Lateral Sclerosis

Cited by 52 publications

References 70 publications

Homeostatic PPARα Signaling Limits Inflammatory Responses to Commensal Microbiota in the Intestine

Homeostatic PPARα Signaling Limits Inflammatory Responses to Commensal Microbiota in the Intestine

Effect of ω-3 supplementation on placental lipid metabolism in overweight and obese women

Proliferation and fission of peroxisomes — An update

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