Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, F-59000 Lille, France.
Laboratory of Critical Care Medicine, Dept Cellular and Molecular Medicine, KU Leuven, University Hospitals Leuven, Herestraat 49 Bus 503, B-3000 Leuven, Belgium.
J Hepatol. 2019 May;70(5):963-973. doi: 10.1016/j.jhep.2018.12.037. Epub 2019 Jan 21.
BACKGROUND & 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. 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.
尽管人们已经了解了炎症在抵御感染方面的作用，但对脓毒症引起的代谢变化的贡献仍知之甚少。脓毒症会引发脂质介质的释放，其中许多介质会激活核受体，如过氧化物酶体增殖物激活受体（PPAR）α，该受体既能控制脂质代谢，又能控制炎症。我们旨在阐明肝 PPARα 在脓毒症反应中的先前未知作用。
在不同的细胞特异性 Ppara 缺陷模型及其对照中，通过腹腔内注射大肠杆菌来诱导脓毒症。使用生化、转录组和功能测定来分析全身和肝脏的代谢反应。分析了来自择期手术和危重病患者的肝脏中 PPARα 的表达，并将其与肝基因表达和血液参数相关联。
在细菌感染时，全身和非造血细胞特异性的 Ppara 缺陷均降低了小鼠的存活率。脓毒症 Ppara 缺陷小鼠的肝脏表现出从葡萄糖向脂质利用的代谢转变受损，导致更严重的低血糖、酮血症诱导受损以及由于参与脂肪酸分解和酮生成的基因表达降低而导致的脂肪变性增加。肝细胞特异性敲除 PPARα 会损害对脓毒症的代谢反应，并足以降低细菌感染时的存活率。危重病患者的肝 PPARA 表达较低，与脂质代谢基因的表达呈正相关，但与系统性炎症标志物无关。
在脓毒症期间，肝细胞中的 Ppara 缺陷是有害的，因为它会损害从葡萄糖向 FA 利用的适应性代谢转变。肝细胞中 PPARα 的代谢控制在宿主抵御感染方面起着关键作用。
作为危重病患者的主要死亡原因，脓毒症仍然是一个缺乏有效治疗方法的主要健康问题。尽管目前的临床文献表明炎症的作用很重要，但脓毒症的代谢方面大多被忽视。在这里，我们显示由于核受体 PPARα 在肝脏中的缺陷导致代谢反应受损的小鼠在细菌感染后表现出更高的死亡率，尽管炎症反应相似，这表明代谢干预可能是改善脓毒症结局的可行策略。
