Hepatic PPARα is critical in the metabolic adaptation to sepsis.

Détails

ID Serval
serval:BIB_F5EBA75845CC
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Hepatic PPARα is critical in the metabolic adaptation to sepsis.
Périodique
Journal of hepatology
Auteur(s)
Paumelle R., Haas J.T., Hennuyer N., Baugé E., Deleye Y., Mesotten D., Langouche L., Vanhoutte J., Cudejko C., Wouters K., Hannou S.A., Legry V., Lancel S., Lalloyer F., Polizzi A., Smati S., Gourdy P., Vallez E., Bouchaert E., Derudas B., Dehondt H., Gheeraert C., Fleury S., Tailleux A., Montagner A., Wahli W., Van Den Berghe G., Guillou H., Dombrowicz D., Staels B.
ISSN
1600-0641 (Electronic)
ISSN-L
0168-8278
Statut éditorial
Publié
Date de publication
05/2019
Peer-reviewed
Oui
Volume
70
Numéro
5
Pages
963-973
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
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)α, which controls both lipid metabolism and inflammation. We aimed to elucidate the previously unknown role of hepatic PPARα in the response to sepsis.
Sepsis was induced by intraperitoneal injection of Escherichia coli in different models of cell-specific Ppara-deficiency and their controls. The systemic and hepatic metabolic response was analyzed using biochemical, transcriptomic and functional assays. PPARα expression was analyzed in livers from elective surgery and critically ill patients and correlated with hepatic gene expression and blood parameters.
Both whole body and non-hematopoietic Ppara-deficiency in mice decreased survival upon bacterial infection. Livers of septic Ppara-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 PPARα impaired the metabolic response to sepsis and was sufficient to decrease survival upon bacterial infection. Hepatic PPARA expression was lower in critically ill patients and correlated positively with expression of lipid metabolism genes, but not with systemic inflammatory markers.
During sepsis, Ppara-deficiency in hepatocytes is deleterious as it impairs the adaptive metabolic shift from glucose to FA utilization. Metabolic control by PPARα in hepatocytes plays a key role in the host defense against infection.
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 PPARα 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.
Mots-clé
Hepatocytes, Inflammation, Metabolism, Nuclear receptors, Sepsis
Pubmed
Web of science
Création de la notice
01/03/2019 13:28
Dernière modification de la notice
21/08/2019 6:37
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