Metabolic injury-induced NLRP3 inflammasome activation dampens phospholipid degradation

Abstract The collateral effects of obesity/metabolic syndrome include inflammation and renal function decline. As renal disease in obesity can occur independently of hypertension and diabetes, other yet undefined causal pathological pathways must be present. Our study elucidate novel pathological pa...

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Autores principales:	Elena Rampanelli, Evelyn Orsó, Peter Ochodnicky, Gerhard Liebisch, Pieter J. Bakker, Nike Claessen, Loes M. Butter, Marius A. van den Bergh Weerman, Sandrine Florquin, Gerd Schmitz, Jaklien C. Leemans
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2577425c3c0b44beacac710531476209
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spelling	oai:doaj.org-article:2577425c3c0b44beacac7105314762092021-12-02T15:05:51ZMetabolic injury-induced NLRP3 inflammasome activation dampens phospholipid degradation10.1038/s41598-017-01994-92045-2322https://doaj.org/article/2577425c3c0b44beacac7105314762092017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01994-9https://doaj.org/toc/2045-2322Abstract The collateral effects of obesity/metabolic syndrome include inflammation and renal function decline. As renal disease in obesity can occur independently of hypertension and diabetes, other yet undefined causal pathological pathways must be present. Our study elucidate novel pathological pathways of metabolic renal injury through LDL-induced lipotoxicity and metainflammation. Our in vitro and in vivo analysis revealed a direct lipotoxic effect of metabolic overloading on tubular renal cells through a multifaceted mechanism that includes intralysosomal lipid amassing, lysosomal dysfunction, oxidative stress, and tubular dysfunction. The combination of these endogenous metabolic injuries culminated in the activation of the innate immune NLRP3 inflammasome complex. By inhibiting the sirtuin-1/LKB1/AMPK pathway, NLRP3 inflammasome dampened lipid breakdown, thereby worsening the LDL-induced intratubular phospholipid accumulation. Consequently, the presence of NLRP3 exacerbated tubular oxidative stress, mitochondrial damage and malabsorption during overnutrition. Altogether, our data demonstrate a causal link between LDL and tubular damage and the creation of a vicious cycle of excessive nutrients-NLRP3 activation-catabolism inhibition during metabolic kidney injury. Hence, this study strongly highlights the importance of renal epithelium in lipid handling and recognizes the role of NLRP3 as a central hub in metainflammation and immunometabolism in parenchymal non-immune cells.Elena RampanelliEvelyn OrsóPeter OchodnickyGerhard LiebischPieter J. BakkerNike ClaessenLoes M. ButterMarius A. van den Bergh WeermanSandrine FlorquinGerd SchmitzJaklien C. LeemansNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Elena Rampanelli Evelyn Orsó Peter Ochodnicky Gerhard Liebisch Pieter J. Bakker Nike Claessen Loes M. Butter Marius A. van den Bergh Weerman Sandrine Florquin Gerd Schmitz Jaklien C. Leemans Metabolic injury-induced NLRP3 inflammasome activation dampens phospholipid degradation
description	Abstract The collateral effects of obesity/metabolic syndrome include inflammation and renal function decline. As renal disease in obesity can occur independently of hypertension and diabetes, other yet undefined causal pathological pathways must be present. Our study elucidate novel pathological pathways of metabolic renal injury through LDL-induced lipotoxicity and metainflammation. Our in vitro and in vivo analysis revealed a direct lipotoxic effect of metabolic overloading on tubular renal cells through a multifaceted mechanism that includes intralysosomal lipid amassing, lysosomal dysfunction, oxidative stress, and tubular dysfunction. The combination of these endogenous metabolic injuries culminated in the activation of the innate immune NLRP3 inflammasome complex. By inhibiting the sirtuin-1/LKB1/AMPK pathway, NLRP3 inflammasome dampened lipid breakdown, thereby worsening the LDL-induced intratubular phospholipid accumulation. Consequently, the presence of NLRP3 exacerbated tubular oxidative stress, mitochondrial damage and malabsorption during overnutrition. Altogether, our data demonstrate a causal link between LDL and tubular damage and the creation of a vicious cycle of excessive nutrients-NLRP3 activation-catabolism inhibition during metabolic kidney injury. Hence, this study strongly highlights the importance of renal epithelium in lipid handling and recognizes the role of NLRP3 as a central hub in metainflammation and immunometabolism in parenchymal non-immune cells.
format	article
author	Elena Rampanelli Evelyn Orsó Peter Ochodnicky Gerhard Liebisch Pieter J. Bakker Nike Claessen Loes M. Butter Marius A. van den Bergh Weerman Sandrine Florquin Gerd Schmitz Jaklien C. Leemans
author_facet	Elena Rampanelli Evelyn Orsó Peter Ochodnicky Gerhard Liebisch Pieter J. Bakker Nike Claessen Loes M. Butter Marius A. van den Bergh Weerman Sandrine Florquin Gerd Schmitz Jaklien C. Leemans
author_sort	Elena Rampanelli
title	Metabolic injury-induced NLRP3 inflammasome activation dampens phospholipid degradation
title_short	Metabolic injury-induced NLRP3 inflammasome activation dampens phospholipid degradation
title_full	Metabolic injury-induced NLRP3 inflammasome activation dampens phospholipid degradation
title_fullStr	Metabolic injury-induced NLRP3 inflammasome activation dampens phospholipid degradation
title_full_unstemmed	Metabolic injury-induced NLRP3 inflammasome activation dampens phospholipid degradation
title_sort	metabolic injury-induced nlrp3 inflammasome activation dampens phospholipid degradation
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/2577425c3c0b44beacac710531476209
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Metabolic injury-induced NLRP3 inflammasome activation dampens phospholipid degradation

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