The lipid biology of sepsis

Abstract

Sepsis, defined as the dysregulated immune response to an infection leading to organ dysfunction, is one of the leading causes of mortality around the globe. Despite the significant progress in delineating the underlying mechanisms of sepsis pathogenesis, there are currently no effective treatments or specific diagnostic biomarkers in the clinical setting. The perturbation of cell signaling mechanisms, inadequate inflammation resolution, and energy imbalance, all of which are altered during sepsis, are also known to lead to defective lipid metabolism. The use of lipids as biomarkers with high specificity and sensitivity may aid in early diagnosis and guide clinical decision making. In addition, identifying the link between specific lipid signatures and their role in sepsis pathology may lead to novel therapeutics. In this review, we discuss the recent evidence on dysregulated lipid metabolism both in experimental and human sepsis focused on bioactive lipids, fatty acids, and cholesterol as well as the enzymes regulating their levels during sepsis. We highlight not only their potential roles in sepsis pathogenesis but also the possibility of using these respective lipid compounds as diagnostic and prognostic biomarkers of sepsis.

Keywords: bioactive lipids; biomarkers; cholesterol; energy imbalance; fatty acids; inflammation; lipid metabolism; prognostics; resolution; sepsis pathogenesis.

Graphical abstract

Fig. 1

Eicosanoids and SPMs in sepsis. Sepsis leads to either increased or decreased (red arrows) eicosanoid and SPM production. Secretory phospholipase A2 (sPLA₂) activity is increased to liberate arachidonic (AA) from plasma phospholipids, and then inducible cyclooxygenase 2 (COX2) activity results in elevated production of cyclooxygenase-derived eicosanoids. Eicosanoids are mediators of proinflammatory mechanisms during sepsis. Proinflammatory mechanisms are counter-regulated by SPMs, which aid in the recovery of sepsis. EPA, DHA, and DPA derived SPMs are increased leading to reduction in inflammatory damage. COX1/2, cyclooxygenase 1/2; CYP450, cytochrome P450; cys-LT, cysteinyl leukotriene; DHET, dihydroxyeicosatrienoic acid; EET, epoxyeicosatrienoic acid; LOX, lipoxygenase; LTB₄, leukotriene B₄; PGD₂, prostaglandin D₂; PGE₂, prostaglandin E₂; PGF_2α, prostaglandin F_2α; RvD1-6, resolvin D 1–6; RvE1-3, resolvin E 1–3; RvT 1–4, resolvin T 1–4; sPLA₂, secretory phospholipase A₂; TXB₂, thromboxane B2.

Fig. 2

Lipids altered in sepsis. Sepsis induces alterations in lipid signaling mechanisms (gray boxes). Red arrows indicated up- or downregulated lipids (big red arrows) and enzymes (small red arrows) relevant to respective lipid biosynthesis that are evident in sepsis. 2-AG, 2-arachidonoylglycerol; 2-ClFA, 2-chlorofatty acid; 2-ClFALD, 2-chlorofatty aldehyde; AA, arachidonic acid; AEA, N-arachidonoylethanolamine; ATX, autotaxin; CB1/2, cannabinoid receptor 1/2; CDase, ceramidase; CE, cholesterol ester; Cer, ceramide; CerS, ceramide synthase; CETP, cholesteryl ester transfer protein; DAG, diacylglycerol; FC, free cholesterol; FFAH, fatty acid amide hydrolase; GCS, glucosylceramide synthase; Gly-Cer, glycosylated ceramide; HOCl, hypochlorous acid; LPA, lysophosphatidic acid; LPC, lysophosphatidylcholine; LPCAT, lysophosphatidylcholine acyltransferase; LPD, lysophospholipase D; LPS, lipopolysaccharide; LTA, lipoteichoic acid; MPO, myeloperoxidase; NAPE, N-acyl phosphatidylethanolamine; PA, phosphatidic acid; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PLTP, phospholipid transfer protein; S1P, sphingosine-1-phosphate; SMase, sphingomyelinase; SMS, sphingomyelin synthase; Sph, sphingosine; Sphk1/2, sphingosine kinase 1/2; sPLA₂, secretory phospholipases A2; SPPase, S1P-phosphatase.