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Role of obesity in the release of extracellular nucleosomes in acute pancreatitis: a clinical and experimental study

International Journal of Obesity volume 43, pages 158–168 (2019)Cite this article

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Abstract

Background/objectives

A high body mass index increases the risk of severe pancreatitis and associated mortality. Our aims were: (1) To determine whether obesity affects the release of extracellular nucleosomes in patients with pancreatitis; (2) To determine whether pancreatic ascites confers lipotoxicity and triggers the release of extracellular nucleosomes in lean and obese rats.

Methods

DNA and nucleosomes were determined in plasma from patients with mild or moderately severe acute pancreatitis either with normal or high body mass index (BMI). Lipids from pancreatic ascites from lean and obese rats were analyzed and the associated toxicity measured in vitro in RAW 264.7 macrophages. The inflammatory response, extracellular DNA and nucleosomes were determined in lean or obese rats with pancreatitis after peritoneal lavage.

Results

Nucleosome levels in plasma from obese patients with mild pancreatitis were higher than in normal BMI patients; these levels markedly increased in obese patients with moderately severe pancreatitis vs. those with normal BMI. Ascites from obese rats exhibited high levels of palmitic, oleic, stearic, and arachidonic acids. Necrosis and histone 4 citrullination—marker of extracellular traps—increased in macrophages incubated with ascites from obese rats but not with ascites from lean rats. Peritoneal lavage abrogated the increase in DNA and nucleosomes in plasma from lean or obese rats with pancreatitis. It prevented fat necrosis and induction of HIF-related genes in lung.

Conclusions

Extracellular nucleosomes are intensely released in obese patients with acute pancreatitis. Pancreatitis-associated ascitic fluid triggers the release of extracellular nucleosomes in rats with severe pancreatitis.

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Acknowledgements

We thank Ms. Landy Menzies for revising the manuscript. This work was supported by Grant SAF2012-39694 and SAF2015-71208-R with FEDER funds from the Spanish Ministry of Economy and Competitiveness to J.S., and by funds from a fellowship of the Group of Pancreas from the Asociación Española de Gastroenterología (AEG); I.F. was recipient of a fellowship from “Programa de Doutorado Sanduíche do Exterior (PDSE)” that belongs to the “Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Research in F.H laboratory is funded by DK095359 and ES04699.

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Authors and Affiliations

  1. Department of Physiology, School of Pharmacy, University of Valencia, Av. Vicente Andrés Estellés s/n, 46100, Burjasot, Valencia, Spain

    Salvador Pérez, Isabela Finamor, Pablo Martí-Andrés, Javier Pereda & Juan Sastre

  2. Department of Physiology and Pharmacology, Federal University of Santa Maria (UFSM), 1000, Santa Maria, Brazil

    Isabela Finamor

  3. Department of Chemistry, University of Aveiro, 3810-193, Aveiro, Portugal

    Ana Campos & Rosário Domingues

  4. Department of Nutrition, University of California Davis, One Shields Ave, Davis, CA, 95616, USA

    Fawaz Haj

  5. Department of Surgery, University of Valencia, University Clinic Hospital, Av. Blasco Ibañez 15, 46010, Valencia, Spain

    Luis Sabater

  6. Department of Gastroenterology, University General Hospital of Alicante, Institute of Sanitary and Biomedical Research of Alicante (ISABIAL), Alicante, Spain

    Enrique de-Madaria

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Pérez, S., Finamor, I., Martí-Andrés, P. et al. Role of obesity in the release of extracellular nucleosomes in acute pancreatitis: a clinical and experimental study. Int J Obes 43, 158–168 (2019). https://doi.org/10.1038/s41366-018-0073-6

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