@article{14f7671d259a41eca8eb1520ec3739c3,
title = "Hepatic PPARα is critical in the metabolic adaptation to sepsis",
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.",
keywords = "Nuclear receptors, Sepsis, Metabolism, Hepatocytes, Inflammation, PROLIFERATOR-ACTIVATED RECEPTORS, INTENSIVE INSULIN THERAPY, FATTY-ACID OXIDATION, GENE-EXPRESSION, PROTECTS, INFLAMMATION, LIVER, TOLERANCE, BACTERIAL, SURVIVAL",
author = "Rejane Paumelle and Haas, {Joel T.} and Nathalie Hennuyer and Eric Bauge and Yann Deleye and Dieter Mesotten and Lies Langouche and Jonathan Vanhoutte and Celine Cudejko and Kristiaan Wouters and Hannou, {Sarah Anissa} and Vanessa Legry and Steve Lancel and Fanny Lalloyer and Arnaud Polizzi and Sarra Smati and Pierre Gourdy and Emmanuelle Vallez and Emmanuel Bouchaert and Bruno Derudas and Helene Dehondt and Celine Gheeraert and Sebastien Fleury and Anne Tailleux and Alexandra Montagner and Walter Wahli and {Van den Berghe}, Greet and Herve Guillou and David Dombrowicz and Bart Staels",
note = "Funding Information: This work was supported by grants from European Genomic Institute for Diabetes (EGID, ANR-10-LABX-46), the Conseil r{\'e}gional Nord Pas-de-Calais and the Fonds europ{\'e}ens de d{\'e}veloppement r{\'e}gional (FEDER). J. Haas was supported by the European Molecular Biology Organization (EMBO) Long-Term Fellowship (ALTF2014-277), Y. Deleye by a doctoral fellowship from the Nouvelle Soci{\'e}t{\'e} Fran{\c c}aise d'Ath{\'e}roscl{\'e}rose, K. Wouters by European FP7 Postdoctoral fellowship (PIEF-GA-2009-235221), EFSD/GlaxoSmithKline Research and European Atherosclerosis Society grants. D. Mesotten is a senior clinical investigator for the Research Foundation – Flanders. G. Van den Berghe receives research financing through the Methusalem program (Flemish government) and holds an “ERC Advanced Grant”. W. Wahli was supported by the Lee Kong Chian School of Medicine, Nanyang Technological University Singapore Start-Up Grant and holds a Chaire d'Excellence Pierre de Fermat (Toulouse). H. Guillou is supported by grants from R{\'e}gion Occitanie and ANR “Hepatokind”. B. Staels holds an “ERC advanced Grant” (694717). We thank A. Lecluse, C. Paquet, A. Lucas, C. Rommens (Inserm U1011) for technical assistance. Funding Information: This work was supported by grants from European Genomic Institute for Diabetes (EGID, ANR-10-LABX-46 ), the Conseil r{\'e}gional Nord Pas-de-Calais and the Fonds europ{\'e}ens de d{\'e}veloppement r{\'e}gional (FEDER). J. Haas was supported by the European Molecular Biology Organization (EMBO) Long-Term Fellowship (ALTF2014-277), Y. Deleye by a doctoral fellowship from the Nouvelle Soci{\'e}t{\'e} Fran{\c c}aise d{\textquoteright}Ath{\'e}roscl{\'e}rose , K. Wouters by European FP7 Postdoctoral fellowship (PIEF-GA-2009-235221), EFSD/GlaxoSmithKline Research and European Atherosclerosis Society grants. D. Mesotten is a senior clinical investigator for the Research Foundation – Flanders. G. Van den Berghe receives research financing through the Methusalem program (Flemish government) and holds an “ERC Advanced Grant”. W. Wahli was supported by the Lee Kong Chian School of Medicine , Nanyang Technological University Singapore Start-Up Grant and holds a Chaire d{\textquoteright}Excellence Pierre de Fermat (Toulouse). H. Guillou is supported by grants from R{\'e}gion Occitanie and ANR “Hepatokind”. B. Staels holds an “ERC advanced Grant” (694717). Publisher Copyright: {\textcopyright} 2019 European Association for the Study of the Liver",
year = "2019",
month = may,
doi = "10.1016/j.jhep.2018.12.037",
language = "English",
volume = "70",
pages = "963--973",
journal = "Journal of Hepatology",
issn = "0168-8278",
publisher = "Elsevier Science",
number = "5",
}