Unsaturated fatty acids prevent activation of NLRP3 inflammasome in human monocytes/macrophages

L’homme, Laurent; Esser, Nathalie; Riva, Laura; Scheen, André; Paquot, Nicolas; Piette, Jacques; Legrand-Poels, Sylvie

doi:10.1194/jlr.m037861

Cited by 128 publications

(114 citation statements)

References 60 publications

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“…This effect of IVA337 might be due to PPARδ because it was previously shown that PPARδ activation decreases the expression of inflammasome components (NLRP3, caspase1, and IL‐1) when stimulated with palmitate (a saturated fatty acid) and lipopolysaccharides in hepatocytes 32. This effect could also be due to the PPARγ effect on SCD1 because saturated fatty acids activate the inflammasome whereas MUFAs inhibit the inflammasome components 26, 38. Overall, these results indicate that activation of PPARα, PPARδ, and PPARγ in the hepatocytes would contribute to the antisteatotic and anti‐inflammatory effect of IVA337 in the MCD and foz/foz models.…”

Section: Discussionmentioning

confidence: 97%

“…Achieving anti‐inflammatory effects is desirable not only for control over metabolic syndrome but also to restrain liver inflammation and thereby interrupt liver disease perpetuation and progression. Lipotoxic‐saturated fatty acids activate the inflammasome pathway in hepatocytes and the subsequent release of pro‐inflammatory cytokines, such as IL‐1β and IL‐18 26, 27. NLRP3 is significantly up‐regulated in patients with NASH,28 and inhibition or knockdown of the inflammasome components reduces insulin resistance, steatosis, and fibrosis 29, 30, 31.…”

Section: Discussionmentioning

confidence: 99%

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The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

Wettstein

Luccarini

Poekes

et al. 2017

Hepatology Communications

101

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IVA337 is a pan‐peroxisome proliferator‐activated receptor (PPAR) agonist with moderate and well‐balanced activity on the three PPAR isoforms (α, γ, δ). PPARs are regulators of lipid metabolism, inflammation, insulin resistance, and fibrogenesis. Different single or dual PPAR agonists have been investigated for their therapeutic potential in nonalcoholic steatohepatitis (NASH), a chronic liver condition in which steatosis coexists with necroinflammation, potentially leading to liver fibrosis and cirrhosis. Clinical results have demonstrated variable improvements of histologically assessed hepatic lesions depending on the profile of the tested drug, suggesting that concomitant activation of the three PPAR isoforms would translate into a more substantial therapeutic outcome in patients with NASH. We investigated the effects of IVA337 on several preclinical models reproducing the main metabolic and hepatic features associated with NASH. These models comprised a diet‐induced obesity model (high‐fat/high‐sucrose diet); a methionine‐ and choline‐deficient diet; the foz/foz model; the CCl4‐induced liver fibrosis model (prophylactic and therapeutic) and human primary hepatic stellate cells. IVA337 normalized insulin sensitivity while controlling body weight gain, adiposity index, and serum triglyceride increases; it decreased liver steatosis, inflammation, and ballooning. IVA337 demonstrated preventive and curative effects on fibrosis in the CCl4 model and inhibited proliferation and activation of human hepatic stellate cells, the key cells driving liver fibrogenesis in NASH. Moreover, IVA337 inhibited the expression of (pro)fibrotic and inflammasome genes while increasing the expression of β‐oxidation‐related and fatty acid desaturation‐related genes in both the methionine‐ and choline‐deficient diet and the foz/foz model. For all models, IVA337 displayed an antifibrotic efficacy superior to selective PPARα, PPARδ, or PPARγ agonists. Conclusion: The therapeutic potential of IVA337 for the treatment of patients with NASH is supported by our data. (Hepatology Communications 2017;1:524–537)

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

Wettstein

Luccarini

Poekes

et al. 2017

Hepatology Communications

101

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“…Unsaturated FAs have been shown to inhibit the LPS-induced NF-κB signalling pathway in macrophages [25,34]. Moreover, monounsaturated FAs, such as oleate, protect against various lipotoxic effects of palmitate [35][36][37][38][39]. The protective effects of oleate are reported at concentrations lower or equimolar to that of palmitate.…”

Section: Discussionmentioning

confidence: 99%

Fatty acids from fat cell lipolysis do not activate an inflammatory response but are stored as triacylglycerols in adipose tissue macrophages

et al. 2015

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Aims/hypothesis Activation of macrophages by fatty acids (FAs) is a potential mechanism linking obesity to adipose tissue (AT) inflammation and insulin resistance. Here, we investigated the effects of FAs released during adipocyte lipolysis on AT macrophages (ATMs). Methods Human THP-1 macrophages were treated with media from human multipotent adipose-derived stem (hMADS) adipocytes stimulated with lipolytic drugs. Macrophages were also treated with mixtures of FAs and an inhibitor of Toll-like receptor 4, since this receptor is activated by saturated FAs.Levels of mRNA and the secretion of inflammation-related molecules were measured in macrophages. FA composition was determined in adipocytes, conditioned media and macrophages. The effect of chronic inhibition or acute activation of fat cell lipolysis on ATM response was investigated in vivo in mice. Results Whereas palmitic acid alone activates THP-1, conditioned media from hMADS adipocyte lipolysis had no effect on IL, chemokine and cytokine gene expression, and secretion by macrophages. Mixtures of FAs representing de novo lipogenesis or habitual dietary conditions also had no effect. FAs derived from adipocyte lipolysis were taken up by macrophages and stored as triacylglycerol droplets. In vivo, chronic treatment with an antilipolytic drug did not modify gene expression and number of ATMs in mice with intact or defective Tlr4. Stimulation of adipocyte lipolysis increased storage of neutral lipids by macrophages without change in number and phenotype.

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“…The deleterious effects of visceral adipose tissue might be also related to an up-regulated expression and activation of NLRP3 inflammasome compared to subcutaneous adipose tissue in overweight and obese patients [33,57]. The NLRP3 inflammasome seems to act as a sensor of metabolic danger signals that accumulate during obesity, including high levels of glucose [52], saturated free fatty acids [58,59], lipid intermediates such as ceramides [56] and uric acid [51], and its activation results in IL-1β production and induction of numerous cytokines and chemokines.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…inflammasome [58,59,63] and can prevent its activation by other inducers [59]. The importance of unsaturated fatty acids in mediating inflammation is enhanced by a recent study showing a distinct fatty acid profile between MHO and unhealthy obese individuals, specifically for saturated fatty acids [64].…”

Section: Page 11 Of 24mentioning

confidence: 99%

Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes

Esser

Legrand-Poels

Piette

et al. 2014

Diabetes Research and Clinical Practice

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1,525

1,064

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:It is recognized that a chronic low-grade inflammation and an activation of the immune system are involved in the pathogenesis of obesity-related insulin resistance and type 2 diabetes. Systemic inflammatory markers are risk factors for the development of type 2 diabetes and its macrovascular complications. Adipose tissue, liver, muscle and pancreas are themselves sites of inflammation in presence of obesity. An infiltration of macrophages and other immune cells is observed in these tissues associated with a cell population shift from an anti-inflammatory to a pro-inflammatory profile. These cells are crucial for the production of pro-inflammatory cytokines, which act in an autocrine and paracrine manner to interfere with insulin signaling in peripheral tissues or induce β-cell dysfunction and subsequent insulin deficiency. Particularly, the pro-inflammatory interleukin-1β is implicated in the pathogenesis of type 2 diabetes through the activation of the NLRP3 inflammasome. The objectives of this review are to expose recent data supporting the role of the immune system in the pathogenesis of insulin resistance and type 2 diabetes and to examine various mechanisms underlying this relationship. If type 2 diabetes is an inflammatory disease, anti-inflammarory therapies could have a place in prevention and treatment of type 2 diabetes.

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Unsaturated fatty acids prevent activation of NLRP3 inflammasome in human monocytes/macrophages

Cited by 128 publications

References 60 publications

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

Fatty acids from fat cell lipolysis do not activate an inflammatory response but are stored as triacylglycerols in adipose tissue macrophages

Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes

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