Invalidation of Microsomal Prostaglandin E Synthase-1 (mPGES-1) Reduces Diet-Induced Low-Grade Inflammation and Adiposity

Clément, P.; Guillebaud, Florent; Airault, Coraline; Baril, Nathalie; Barbouche, Rym; Save, Étienne; Gaigé, Stéphanie; Bariohay, B.; Dallaporta, Michel; Troadec, Jean‐Denis

doi:10.3389/fphys.2018.01358

Cited by 12 publications

(12 citation statements)

References 62 publications

(79 reference statements)

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“…ARDS, and thereby prevent ICU admissions and decrease mortality, is based on the role PGE2 has as an inflammatory modulator in viral infections and further literature supporting that targeted PGE2 inhibition enhances antiviral immunity (Ricciotti and Fitzgerald, 2011;Coulombe et al, 2014;Bergqvist et al, 2020) (Figure 2). That PGE2 belongs to the many factors contributing to the uncontrolled inflammation observed in obese individuals adds to our hypothesis (González-Périz and Clària, 2010; Pierre et al, 2018). Besides, mPGES-1 knock-out mice have been shown to reduce diet-induced lowgrade inflammation and adiposity (Pierre et al, 2018).…”

Section: Selective Mpges-1 Inhibition To Attenuate Covid-19 Associatesupporting

confidence: 62%

“…That PGE2 belongs to the many factors contributing to the uncontrolled inflammation observed in obese individuals adds to our hypothesis (González-Périz and Clària, 2010; Pierre et al, 2018). Besides, mPGES-1 knock-out mice have been shown to reduce diet-induced lowgrade inflammation and adiposity (Pierre et al, 2018).…”

Section: Selective Mpges-1 Inhibition To Attenuate Covid-19 Associatesupporting

confidence: 62%

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Hypothesis: mPGES-1-Derived Prostaglandin E2, a So Far Missing Link in COVID-19 Pathophysiology?

Smeitink¹,

Jiang²,

Pecheritsyna³

et al. 2020

Preprint

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With frequencies varying up to 20%, treatment resistant pulmonary failure is a major life-threatening complication in COVID-19 (SARS-CoV-2, HCoV19) disease pathology. Both acute respiratory distress syndrome (ARDS), proposed to be caused by an over-reacting immune system which floods the lung with edema, a liquid consisting of inflammatory cells, and diminished lung perfusion, have been postulated to cause this treatment resistant lung failure. Aging, co-morbidities, male gender and obesity are pre-existing factors associated with the more severe outcome. Thrombosis is more frequently observed than usually seen during ICU admission. Different hypotheses explaining the pathophysiological cascade leading to fast progressing severe COVID-19 disease and how to counteract it have been proposed. A variety of intervention studies to control severity are ongoing or planned. Not suggested so far, we here hypothesize that the inflammatory lipid modulator prostaglandin E2 (PGE2) executes a prominent role in COVID-19 pathophysiology. Based on this we suggest measuring PGE2 in patients and evaluating selective inhibition of the human microsomal prostaglandin E synthase-1 (mPGES-1) as a potential innovative therapeutic approach in this devastating condition for which sonlicromanol, a drug currently in phase 2b studies for mitochondrial disease, is a candidate.

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Section: Selective Mpges-1 Inhibition To Attenuate Covid-19 Associatesupporting

confidence: 62%

Section: Selective Mpges-1 Inhibition To Attenuate Covid-19 Associatesupporting

confidence: 62%

Hypothesis: mPGES-1-Derived Prostaglandin E2, a So Far Missing Link in COVID-19 Pathophysiology?

Smeitink¹,

Jiang²,

Pecheritsyna³

et al. 2020

Preprint

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“…Furthermore, microsomal PGE synthase-1 (mPGES-1) is an enzyme that specifically catalyzes the final step of PGE 2 biosynthesis. The mPGES-1 knockout mice fed a HFD had lower body weight gain and reduced adiposity, which were accompanied by a decrease in adipose tissue inflammation compared to the inflammation of littermate control mice [31]. In addition, the upregulation of adipocyte COX-2, PGE 2 , and EP3 signaling, during obesity-associated adipocyte hypertrophy and hypoxia, was causally linked to the augmented gene expression and protein production of inflammatory adipokines.…”

Section: Cox-2-derived Pgs and Obesity Associated Complicationsmentioning

confidence: 99%

The Dualistic Effect of COX-2-Mediated Signaling in Obesity and Insulin Resistance

Chan

Liao

Hsieh

2019

IJMS

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Obesity and insulin resistance are two major risk factors for the development of metabolic syndrome, type 2 diabetes and associated cardiovascular diseases (CVDs). Cyclooxygenase (COX), a rate-limiting enzyme responsible for the biosynthesis of prostaglandins (PGs), exists in two isoforms: COX-1, the constitutive form, and COX-2, mainly the inducible form. COX-2 is the key enzyme in eicosanoid metabolism that converts eicosanoids into a number of PGs, including PGD2, PGE2, PGF2α, and prostacyclin (PGI2), all of which exert diverse hormone-like effects via autocrine or paracrine mechanisms. The COX-2 gene and immunoreactive proteins have been documented to be highly expressed and elevated in adipose tissue (AT) under morbid obesity conditions. On the other hand, the environmental stress-induced expression and constitutive over-expression of COX-2 have been reported to play distinctive roles under different pathological and physiological conditions; i.e., over-expression of the COX-2 gene in white AT (WAT) has been shown to induce de novo brown AT (BAT) recruitment in WAT and then facilitate systemic energy expenditure to protect mice against high-fat diet-induced obesity. Hepatic COX-2 expression was found to protect against diet-induced steatosis, obesity, and insulin resistance. However, COX-2 activation in the epidydimal AT is strongly correlated with the development of AT inflammation, insulin resistance, and fatty liver in high-fat-diet-induced obese rats. This review will provide updated information regarding the role of COX-2-derived signals in the regulation of energy metabolism and the pathogenesis of obesity and MS.

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“…The results of a retrospective cohort study that recruited 402 PD patients demonstrated that the serum C-reactive protein level is an independent predictor of technique failure (34), suggesting that systemic inflammation is associated with technique survival. mPGES-1/PGE2 plays a critical role in the progression of multiple diseases via proinflammatory mechanisms (28,35,36). We explored the effect between mPGES-1/PGE2 signaling and the NLRP3 inflammasome in high-glucose-stimulated RPMCs.…”

Section: Discussionmentioning

confidence: 99%

Enhanced mPGES-1 Contributes to PD-Related Peritoneal Fibrosis via Activation of the NLRP3 Inflammasome

Luo

Zheng

et al. 2021

Front. Med.

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Background: Microsomal prostaglandin E synthase-1 (mPGES-1)-derived prostaglandin E2 (PGE2) is a chief mediator of inflammation. However, the role and mechanism of mPGES-1 in peritoneal dialysis (PD)-associated peritoneal fibrosis have not been investigated.Material and Methods: In PD patients, mPGES-1 expression in peritoneum tissues and the levels of PGE2, IL-1β, and IL-18 in the dialysate were examined. In rat peritoneal mesothelial cells (RPMCs), the regulation and function of mPGES-1 and NLRP3 inflammasome were investigated. The expression of extracellular matrix proteins and the components of NLRP3 inflammasome were detected by Western blotting or real-time quantitative PCR.Results: In PD patients with ultrafiltration failure (UFF), mPGES-1 was enhanced in the peritoneum, which was associated with the degree of peritoneal fibrosis. Accordingly, the intraperitoneal PGE2 levels were also positively related to the PD duration, serum C-reactive protein levels, and serum creatinine levels in incident PD patients. In RPMCs, high-glucose treatment significantly induced mPGES-1 expression and PGE2 secretion without affecting the expressions of mPGES-2 and cPGES. Inhibition of mPGES-1 via short hairpin RNA significantly ameliorated the expression of extracellular matrix proteins of RPMCs induced by high glucose. Additionally, high glucose markedly activated NLRP3 inflammasome in RPMCs that was blunted by mPGES-1 inhibition. Furthermore, silencing NLRP3 with siRNA significantly abrogated the expression of extracellular matrix proteins in RPMCs treated with high glucose. Finally, we observed increased IL-1β and IL-18 levels in the dialysate of incident PD patients, showing a positive correlation with PGE2.Conclusion: These data demonstrate that mPGES-1-derived PGE2 plays a critical role in PD-associated peritoneal fibrosis through activation of the NLRP3 inflammasome. Targeting mPGES-1 may offer a novel strategy to treat peritoneal fibrosis during PD.

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Invalidation of Microsomal Prostaglandin E Synthase-1 (mPGES-1) Reduces Diet-Induced Low-Grade Inflammation and Adiposity

Cited by 12 publications

References 62 publications

Hypothesis: mPGES-1-Derived Prostaglandin E2, a So Far Missing Link in COVID-19 Pathophysiology?

Hypothesis: mPGES-1-Derived Prostaglandin E2, a So Far Missing Link in COVID-19 Pathophysiology?

The Dualistic Effect of COX-2-Mediated Signaling in Obesity and Insulin Resistance

Enhanced mPGES-1 Contributes to PD-Related Peritoneal Fibrosis via Activation of the NLRP3 Inflammasome

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