Hepatic PPARalpha is critical in the metabolic adaptation to sepsis

Réjane Paumelle (1) , Joël Haas (1) , Nathalie Hennuyer (1) , Eric Baugé (1) , Yann Deleye (1) , Dieter Mesotten (2) , Lies Langouche (2) , Jonathan Vanhoutte (1) , Céline Cudejko (1) , Kristiaan Wouters (3) , Sarah Anissa Hannou (1) , Vanessa Legry (1) , Steve Lancel (1) , Fanny Lalloyer (1) , Arnaud Polizzi (4) , Sarra Smati (5) , Pierre Gourdy (6) , Emmanuelle Vallez (1) , Emmanuel Bouchaert (1) , Bruno Derudas (1) , Hélène Dehondt (1) , Celine Gheeraert (1) , Sébastien Fleury (1) , Anne Tailleux (1) , Alexandra Montagner (5, 6) , Walter Wahli (7, 8) , Greet van den Berghe (2) , David Dombrowicz (1) , Hervé Guillou , Bart Staels (1)

1 RNMCD - Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011
2 Department of Intensive care Medicine
3 Maastricht University [Maastricht]
4 ToxAlim-TIM - Toxicologie Intégrative & Métabolisme
5 ToxAlim - ToxAlim
6 I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
7 CIG - Center for Integrative Genomics - Institute of Bioinformatics, Génopode
8 Lee Kong Chian School of Medicine

Background and 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. However, the role of hepatic PPARalpha in the response to sepsis is unknown. Methods: Sepsis was induced by intraperitoneal injection of Escherichia coli in different models of cell-specific Pparalpha-deficiency and their controls. The systemic and hepatic metabolic response was analysed using biochemical, transcriptomic and functional assays. PPARalpha 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 Pparalpha-deficiency in mice decreased survival upon bacterial infection. Livers of septic Pparalpha-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 PPARalpha 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. Conclusion: Metabolic control by PPARalpha in hepatocytes plays a key role in the host defense to infection.

Mots clés: inflammation; nuclear receptors; sepsis; metabolism; hepatocytes

Domaines: Maladies infectieuses; Biochimie, Biologie Moléculaire

Réjane Paumelle, Joël Haas, Nathalie Hennuyer, Eric Baugé, Yann Deleye, et al.. Hepatic PPARalpha is critical in the metabolic adaptation to sepsis. Journal of Hepatology, 2019, 70 (5), pp.963-973. ⟨10.1016/j.jhep.2018.12.037⟩. ⟨inserm-02109735⟩