Activation of peroxisome proliferator-activated receptor-γ protects pancreatic β-cells from cytokine-induced cytotoxicity via NFκB pathway

Kim, Min Jung; Kwon, Kang‐Beom; Koo, Bon-Sun; Han, Mi-Jeong; Song, Mi‐Young; Song, Eun-Kyung; Han, Myung‐Kwan; Park, Jin-Woo; Ryu, Do-Gon; Park, Byung‐Hyun

doi:10.1016/j.biocel.2007.04.005

Cited by 76 publications

(48 citation statements)

References 60 publications

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“…For example, PPAR␥ activation has been shown to induce IB␣ mRNA and protein expression in mouse cardiac tissues (21) and reduces p65 expression in human peripheral monocytes (37). It is also revealed that PPAR␥ activation by its agonists suppresses IB kinase activity in pancreatic acinar AR42J cells (36), whereas it inhibits IL-1␤ and IFN␥-stimulated p65 nuclear translocation and its DNA binding activity in rat pancreatic ␤-cells (38). Therefore, it appears that PPAR␥ activation can influence distinct events in the processes of NF-B signaling in a cell context-specific fashion.…”

Section: Discussionmentioning

confidence: 98%

Opposite Action of Peroxisome Proliferator-activated Receptor-γ in Regulating Renal Inflammation

Wen

Liu

2010

Journal of Biological Chemistry

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Peroxisome proliferator-activated receptor-␥ (PPAR␥) agonists, a new class of antidiabetic agents, have been shown to possess antiinflammatory activity. In this study, we investigated the molecular mechanism by which PPAR␥ agonists inhibit proinflammatory cytokine expression in rat glomerular mesangial cells. Both natural and synthetic PPAR␥ agonists potently inhibited RANTES (regulated upon activation, normal T cell expressed and secreted) and monocyte chemoattractant protein-1 expression induced by TNF-␣ in mesangial cells, which was dependent on NF-B signaling. However, PPAR␥ agonists had little effect on TNF-␣-triggered IB␣ phosphorylation and its subsequent degradation, p65 phosphorylation, and nuclear translocation. In the absence of PPAR␥ ligand, TNF-␣ induced a physical interaction between nuclear p65 and PPAR␥, as demonstrated by co-immunoprecipitation. Such an interaction was mediated by the C-terminal region of p65. Activation of PPAR␥ by its agonist prevented PPAR␥⅐p65 complex formation. Chromatin immunoprecipitation assay revealed that TNF-␣ induced p65 binding to the cis-acting B elements in rat RANTES promoter, whereas disruption of PPAR␥⅐p65 by its agonist blocked p65 interaction with its cognate B sites. Knockdown of PPAR␥ via siRNA strategy completely abolished TNF-␣-mediated p65 binding to B sites and negated RANTES induction, suggesting that unliganded PPAR␥ is obligatory for NF-B signaling. Consistently, overexpression of PPAR␥ in the absence of its ligand sensitized mesangial cells to TNF-␣ stimulation. These results uncover a paradoxical action of the unliganded and ligand-activated PPAR␥ in regulating NF-B signaling and demonstrate PPAR␥ ligand as a molecular switch that controls its ability to modulate inflammatory responses in opposite directions.Peroxisome proliferator-activated receptor-␥ (PPAR␥), 2 a ligand-dependent transcription factor that belongs to a subclass of the nuclear hormone receptor superfamily, plays a pivotal role in regulating a wide variety of biological processes such as insulin sensitivity, immune response, adipogenesis, and glucose homeostasis (1-3). PPAR␥ is also the molecular target of thiazolidinediones, which are insulin-sensitizing drugs that are used clinically in the treatment of type 2 diabetes (3-5). Although the mechanism underlying its insulin sensitization action remains to be fully elucidated, PPAR␥ activation by its agonists is known to negatively regulate the stimulus-dependent production of numerous inflammatory mediators that promote an insulin-resistant state (6 -8). Evidence shows that PPAR␥ agonists are able to inhibit the expression and/or biological effects of tumor necrosis factor-␣ (TNF-␣), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1, and angiotensinogen (9). These studies underscore that the antiinflammatory potential of PPAR␥ agonists may play a crucial role in mediating their beneficial actions.A large body of evidence demonstrates that PPAR␥ agonists also ameliorate renal fibrotic ...

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Section: Discussionmentioning

confidence: 98%

Opposite Action of Peroxisome Proliferator-activated Receptor-γ in Regulating Renal Inflammation

Wen

Liu

2010

Journal of Biological Chemistry

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“…Fatty acids potentiate IL-1-mediated beta cell toxicity [41]. Fatty acids, but not high glucose, markedly reduce human islet peroxisome proliferator-activated receptor (PPAR)γ production [42], and since PPARγ agonists have antiinflammatory properties and protect islets from cytokine toxicity [43], fatty acids may reduce beta cell antiinflammatory defence mechanisms. Of note, fatty acids have not been reported to activate intra-islet innate immunity.…”

Section: Saturated Fatty Acidsmentioning

confidence: 99%

“…Of note, fatty acids have not been reported to activate intra-islet innate immunity. Both inflammatory cytokines and saturated fatty acids cause beta cell apoptosis via the intrinsic pathway, whereas saturated fatty acids also activate an NFκB-and nitric-oxide-independent endoplasmic reticulum stress death pathway [43][44][45].…”

Section: Saturated Fatty Acidsmentioning

confidence: 99%

The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation

Kolb¹,

2009

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The recent major increase in the global incidence of type 2 diabetes suggests that most cases of this disease are caused by changes in environment and lifestyle. All major risk factors for type 2 diabetes (overnutrition, low dietary fibre, sedentary lifestyle, sleep deprivation and depression) have been found to induce local or systemic low-grade inflammation that is usually transient or milder in individuals not at risk for type 2 diabetes. By contrast, inflammatory responses to lifestyle factors are more pronounced and prolonged in individuals at risk of type 2 diabetes and appear to occur also in the pancreatic islets. Chronic low-grade inflammation will eventually lead to overt diabetes if counter-regulatory circuits to inflammation and metabolic stress are compromised because of a genetic and/or epigenetic predisposition. Hence, it is not the lifestyle change per se but a deficient counter-regulatory response in predisposed individuals which is crucial to disease pathogenesis. Novel approaches of intervention may target these deficient defence mechanisms.

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“…This process generated recombinant viruses that were termed Ad-DCD. A virus containing the bacterial b-galactosidase (b-gal) gene under the control of the cytomegalovirus promoter (Ad-b-gal) was then prepared, purified, and titrated as described previously (Kim et al 2007).…”

Section: Preparation Of the Recombinant Adenovirusmentioning

confidence: 99%

Effect of dermcidin, an antimicrobial peptide, on body fat mobilization in normal mice

Kim¹,

Ka²,

Moon³

et al. 2008

Journal of Endocrinology

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Dermcidin (DCD), an antimicrobial peptide that is secreted by sweat glands, is reportedly a human homolog of mouse proteolysis-inducing factor. This study was conducted to investigate the effect of DCD on body fat mobilization. The expression level of DCD in the livers of Ad-DCD-injected mice was higher than in those of Ad-b-galactosidase (Ad-bgal)-injected mice 7 days after injection. In addition, injection with the Ad-DCD virus led to decreased body weight and epididymal fat mass when compared with controls. The plasma triglyceride level was decreased, whereas the free fatty acid and glycerol levels were increased in the Ad-DCDinjected group. Epididymal adipose tissues obtained from Ad-DCD-injected mice consisted of smaller adipocytes than tissues obtained from Ad-b-gal-injected mice. The gene expression profiles revealed an upregulation of hormonesensitive lipase and adipose fatty acid-binding protein, both of which are involved in adipocyte lipolysis, in Ad-DCDinjected mice, and this lipolytic effect of DCD paralleled the increase of circulating tumor necrosis factor-a (TNF-a) level that was observed. The perilipin levels in adipose tissue were decreased in Ad-DCD-injected mice when compared with those of the control mice. Taken together, these results suggest that DCD-mediated body fat reduction might occur as a result of TNF-a-induced downregulation of perilipin in adipose tissue.

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Activation of peroxisome proliferator-activated receptor-γ protects pancreatic β-cells from cytokine-induced cytotoxicity via NFκB pathway

Cited by 76 publications

References 60 publications

Opposite Action of Peroxisome Proliferator-activated Receptor-γ in Regulating Renal Inflammation

Opposite Action of Peroxisome Proliferator-activated Receptor-γ in Regulating Renal Inflammation

The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation

Effect of dermcidin, an antimicrobial peptide, on body fat mobilization in normal mice

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