Paumelle 2019 J Hepatol
Paumelle R, Haas J, Hennuyer N, Bauge E, Deleye Y, Mesotten D, Langouche L, Vanhoutte J, Cudejko C, Wouters K, Hannou SA, 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 (2019) Hepatic PPARΞ± is critical in the metabolic adaptation to sepsis. J Hepatol 70:963-73. |
Paumelle R, Haas J, Hennuyer N, Bauge E, Deleye Y, Mesotten D, Langouche L, Vanhoutte J, Cudejko C, Wouters K, Hannou SA, 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 (2019) J Hepatol
Abstract: 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)Ξ±, which controls both lipid metabolism and inflammation. However, the role of hepatic PPARΞ± in the response to sepsis is unknown.
Sepsis was induced by intraperitoneal injection of Escherichia coli in different models of cell-specific PparΞ±-deficiency and their controls. The systemic and hepatic metabolic response was analysed using biochemical, transcriptomic and functional assays. PPARΞ± expression was analysed 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 PparΞ±-deficiency in mice decreased survival upon bacterial infection. Livers of septic PparΞ±-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 PPARΞ± 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.
Metabolic control by PPARΞ± in hepatocytes plays a key role in the host defense to infection. Lay summary: As the main cause of death of 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 been mostly overlooked. Here, we show that mice with an impaired metabolic response, due to deficiency of the nuclear receptor PPARΞ± 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.
Copyright Β© 2019. Published by Elsevier B.V. β’ Keywords: Hepatocytes, Inflammation, Metabolism, Nuclear receptors, Sepsis β’ Bioblast editor: Plangger M β’ O2k-Network Lab: FR Lille Duez H, FR Lille Lancel Steve
Labels: MiParea: Respiration
Pathology: Infectious, Sepsis
Organism: Human Tissue;cell: Liver Preparation: Homogenate
Coupling state: LEAK, OXPHOS
Pathway: F, N
HRR: Oxygraph-2k
2019-01