Center for Inflammation Research, VIB, Ghent, Belgium.
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
EMBO Mol Med. 2020 Feb 7;12(2):e11319. doi: 10.15252/emmm.201911319. Epub 2020 Jan 9.
Despite intensive research and constant medical progress, sepsis remains one of the most urgent unmet medical needs of today. Most studies have been focused on the inflammatory component of the disease; however, recent advances support the notion that sepsis is accompanied by extensive metabolic perturbations. During times of limited caloric intake and high energy needs, the liver acts as the central metabolic hub in which PPARα is crucial to coordinate the breakdown of fatty acids. The role of hepatic PPARα in liver dysfunction during sepsis has hardly been explored. We demonstrate that sepsis leads to a starvation response that is hindered by the rapid decline of hepatic PPARα levels, causing excess free fatty acids, leading to lipotoxicity, and glycerol. In addition, treatment of mice with the PPARα agonist pemafibrate protects against bacterial sepsis by improving hepatic PPARα function, reducing lipotoxicity and tissue damage. Since lipolysis is also increased in sepsis patients and pemafibrate protects after the onset of sepsis, these findings may point toward new therapeutic leads in sepsis.
尽管进行了深入的研究和不断的医学进步，但脓毒症仍然是当今最紧迫的未满足的医学需求之一。大多数研究都集中在疾病的炎症成分上；然而，最近的进展支持这样一种观点，即脓毒症伴随着广泛的代谢紊乱。在热量摄入有限和能量需求高的情况下，肝脏作为中央代谢枢纽，其中 PPARα 对于协调脂肪酸的分解至关重要。肝脏 PPARα 在脓毒症期间肝功能障碍中的作用几乎没有被探索过。我们证明脓毒症导致饥饿反应，而肝脏 PPARα 水平的迅速下降阻碍了这种反应，导致游离脂肪酸过多，导致脂肪毒性和甘油。此外，用 PPARα 激动剂 pemafibrate 治疗小鼠可通过改善肝脏 PPARα 功能、减少脂肪毒性和组织损伤来预防细菌性脓毒症。由于脓毒症患者的脂肪分解也增加，而 pemafibrate 在脓毒症发作后具有保护作用，这些发现可能为脓毒症提供新的治疗线索。
