Hepatic PPARα is critical in the metabolic adaptation to sepsis

Rejane Paumelle, Joel T. Haas, Nathalie Hennuyer, Eric Bauge, Yann Deleye, Dieter Mesotten, Lies Langouche, Jonathan Vanhoutte, Celine Cudejko, Kristiaan Wouters, Sarah Anissa Hannou, Vanessa Legry, Steve Lancel, Fanny Lalloyer, Arnaud Polizzi, Sarra Smati, Pierre Gourdy, Emmanuelle Vallez, Emmanuel Bouchaert, Bruno DerudasHelene Dehondt, Celine Gheeraert, Sebastien Fleury, Anne Tailleux, Alexandra Montagner, Walter Wahli, Greet Van den Berghe, Herve Guillou, David Dombrowicz, Bart Staels*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Background & Aims: Although the role of inflammation to combat infection is known, the contribution of metabolic changes in response to sepsis is poorly understood. Sepsis induces the release of lipid mediators, many of which activate nuclear receptors such as the peroxisome proliferator-activated receptor (PPAR)alpha, which controls both lipid metabolism and inflammation. We aimed to elucidate the previously unknown role of hepatic PPAR alpha in the response to sepsis.

Methods: Sepsis was induced by intraperitoneal injection of Escherichia coli in different models of cell-specific PPAR alpha-deficiency and their controls. The systemic and hepatic metabolic response was analyzed using biochemical, transcriptomic and functional assays. PPAR alpha expression was analyzed in livers from elective surgery and critically ill patients and correlated with hepatic gene expression and blood parameters.

Results: Both whole body and non-hematopoietic PPAR alpha-deficiency in mice decreased survival upon bacterial infection. Livers of septic PPAR alpha-deficient mice displayed an impaired metabolic shift from glucose to lipid utilization resulting in more severe hypoglycemia, impaired induction of hyperketonemia and increased steatosis due to lower expression of genes involved in fatty acid catabolism and ketogenesis. Hepatocyte-specific deletion of PPAR alpha impaired the metabolic response to sepsis and was sufficient to decrease survival upon bacterial infection. Hepatic PPAR alpha expression was lower in critically ill patients and correlated positively with expression of lipid metabolism genes, but not with systemic inflammatory markers.

Conclusion: During sepsis, PPAR alpha-deficiency in hepatocytes is deleterious as it impairs the adaptive metabolic shift from glucose to FA utilization. Metabolic control by PPAR alpha in hepatocytes plays a key role in the host defense against infection.

Lay summary: As the main cause of death in critically ill patients, sepsis remains a major health issue lacking efficacious therapies. While current clinical literature suggests an important role for inflammation, metabolic aspects of sepsis have mostly been overlooked. Here, we show that mice with an impaired metabolic response, due to deficiency of the nuclear receptor PPAR alpha in the liver, exhibit enhanced mortality upon bacterial infection despite a similar inflammatory response, suggesting that metabolic interventions may be a viable strategy for improving sepsis outcomes. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)963-973
Number of pages11
JournalJournal of Hepatology
Volume70
Issue number5
DOIs
Publication statusPublished - May 2019

Keywords

  • Nuclear receptors
  • Sepsis
  • Metabolism
  • Hepatocytes
  • Inflammation
  • PROLIFERATOR-ACTIVATED RECEPTORS
  • INTENSIVE INSULIN THERAPY
  • FATTY-ACID OXIDATION
  • GENE-EXPRESSION
  • PROTECTS
  • INFLAMMATION
  • LIVER
  • TOLERANCE
  • BACTERIAL
  • SURVIVAL

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