Hepatic PPARα is critical in the metabolic adaptation to sepsis

作者：Réjane Paumelle, J. Haas, N. Hennuyer, E. Baugé, Yann Deleye, D. Mesotten, L. Langouche, Jonathan Vanhoutte, C. Cudejko, K. Wouters, S. Hannou, V. Legry, S. Lancel, F. Lalloyer, A. Polizzi, S. Smati, P. Gourdy, Emmanuelle Vallez, E. Bouchaert, B. Derudas, H. Dehondt, Céline Gheeraert, S. Fleury, A. Tailleux, A. Montagner, W. Wahli, G. Van den Berghe, H. Guillou, D. Dombrowicz, B. Staels · 发表于：Journal of Hepatology · 年份：2019 · DOI：10.1016/j.jhep.2018.12.037 · 被引用次数：82 · 研究领域：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)α, which controls both lipid metabolism and inflammation. However, the role of hepatic PPARα in the response to sepsis is unknown. Methods Sepsis was induced by intraperitoneal injection of Escherichia coli in different models of cell-specific Pparα -deficiency and their controls. The systemic and hepatic metabolic response was analysed using biochemical, transcriptomic and functional assays. PPARα 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 Pparα -deficiency in mice decreased survival upon bacterial infection. Livers of septic Pparα -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...