Metabolic injury-induced NLRP3 inflammasome activation dampens phospholipid degradation

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...

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Vydané v:Scientific reports Ročník 7; číslo 1; s. 2861 - 13
Hlavní autori: Rampanelli, Elena, Orsó, Evelyn, Ochodnicky, Peter, Liebisch, Gerhard, Bakker, Pieter J., Claessen, Nike, Butter, Loes M., van den Bergh Weerman, Marius A., Florquin, Sandrine, Schmitz, Gerd, Leemans, Jaklien C.
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: London Nature Publishing Group UK 06.06.2017
Nature Publishing Group
Nature Portfolio
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13/109
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631/80/86/2365
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Diabetes mellitus
Epithelial Cells - metabolism
Epithelium
Humanities and Social Sciences
Humans
Hypertension
Inflammasomes
Inflammasomes - metabolism
Kidney Tubules - metabolism
Lipid Metabolism
Lipids
Lipoproteins, LDL - metabolism
LKB1 protein
Low density lipoprotein
Lysosomes - metabolism
Malabsorption
Metabolic Diseases - metabolism
Metabolic disorders
Metabolic Networks and Pathways
Metabolic rate
Metabolic syndrome
Metabolism
Mitochondria
Models, Biological
multidisciplinary
NLR Family, Pyrin Domain-Containing 3 Protein - metabolism
Nutrient cycles
Nutrients
Obesity
Overnutrition
Oxidative Stress
Phospholipid degradation
Phospholipids - metabolism
Protein-Serine-Threonine Kinases - metabolism
Renal function
Science
Science (multidisciplinary)
Sirtuin 1 - metabolism
ISSN:2045-2322, 2045-2322
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Shrnutí: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.
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-017-01994-9