Lipid and Lipoprotein Dysregulation in Sepsis: Clinical and Mechanistic Insights into Chronic Critical Illness

Abstract

In addition to their well-characterized roles in metabolism, lipids and lipoproteins have pleiotropic effects on the innate immune system. These undergo clinically relevant alterations during sepsis and acute inflammatory responses. High-density lipoprotein (HDL) plays an important role in regulating the immune response by clearing bacterial toxins, supporting corticosteroid release, decreasing platelet aggregation, inhibiting endothelial cell apoptosis, reducing the monocyte inflammatory response, and inhibiting expression of endothelial cell adhesion molecules. It undergoes quantitative as well as qualitative changes which can be measured using the HDL inflammatory index (HII). Pro-inflammatory, or dysfunctional HDL (dysHDL) lacks the ability to perform these functions, and we have also found it to independently predict adverse outcomes and organ failure in sepsis. Another important class of lipids known as specialized pro-resolving mediators (SPMs) positively affect the escalation and resolution of inflammation in a temporal fashion. These undergo phenotypic changes in sepsis and differ significantly between survivors and non-survivors. Certain subsets of sepsis survivors go on to have perilous post-hospitalization courses where this inflammation continues in a low grade fashion. This is associated with immunosuppression in a syndrome of persistent inflammation, immunosuppression, and catabolism syndrome (PICS). The continuous release of tissue damage-related patterns and viral reactivation secondary to immunosuppression feed this chronic cycle of inflammation. Animal data indicate that dysregulation of endogenous lipids and SPMs play important roles in this process. Lipids and their associated pathways have been the target of many clinical trials in recent years which have not shown mortality benefit. These results are limited by patient heterogeneity and poor animal models. Considerations of sepsis phenotypes and novel biomarkers in future trials are important factors to be considered in future research. Further characterization of lipid dysregulation and chronic inflammation during sepsis will aid mortality risk stratification, detection of sepsis, and inform individualized pharmacologic therapies.

Impact of Sepsis on High-Density Lipoprotein Metabolism

“…Both CETP and PLTP are part of the lipid-transfer and LPS-binding proteins ( Hubacek et al, 1997 ; Kirschning et al, 1997 ; Levels et al, 2005 ). CETP can transfer CE via hydrophobic tunnels from HDL to LDL and VLDL, while PLTP transfers PL to HDL ( Zhang et al, 2012 ; Barker et al, 2021 ). PLTP and CETP may protect against endotoxins and were considered to enhance LPS elimination ( Kirschning et al, 1997 ; Cazita et al, 2008 ; Gautier et al, 2008 ).…”

“…Another enzyme involved in lipoprotein metabolism is endothelial lipase, which is a driving factor for hydrolyzation of phospholipids (PL) of HDL particles. Furthermore, CETP transfers CE from HDL to low-density (LDL) and very low-density lipoproteins (VLDL) in exchange for triglycerides (TG), while the phospholipid transfer protein (PLTP) transfers PL from triglyceride-rich lipoproteins to HDL ( Deckert et al, 2017 ; Trinder et al, 2019 ; Tanaka et al, 2020 ; Barker et al, 2021 ). PLTP may also transfer LPS from bacteria to HDL ( Vesy et al, 2000 ).…”

Patient Stratification in Sepsis: Using Metabolomics to Detect Clinical Phenotypes, Sub-Phenotypes and Therapeutic Response

“…For this reason, it has been suggested that HDL particles could have a therapeutic role in the treatment of sepsis [ 54 ]. Three metabolomic studies on adults reported that total cholesterol; non-HDL cholesterol; apolipoprotein (Apo)-A1, a major component of HDL [ 55 ] through which HDL binds to lps [ 56 ]; Apo-B100, a component of LDL, VLDL and intermediate-density lipoprotein (IDL) which is involved in the development of atherosclerosis [ 57 ]; HDL Apo-A1; HDL cholesterol; LDL cholesterol; and HDL-free cholesterol were reduced in sepsis patients compared to intensive care [ 39 ] and healthy controls [ 43 , 44 ], whilst VLDL-free cholesterol, triglycerides (TG) and VLDL triglyceride subfractions 4 and 5, VLDL Apo-B100 and Apo-B100 to Apo-A1 ratio were elevated [ 39 ]. These results suggest decreased neutralisation and clearance of bacterial toxins via the liver [ 58 ], increased TG production, reduced lipoprotein lipase activity and enhanced production or reduced clearance of VLDL [ 55 , 59 ].…”

“…As previously described, HDL is the lipoprotein which possesses the highest affinity for both the Gram-positive and Gram-negative bacterial toxins LTA [ 111 ] and lps [ 54 , 112 ] and binds them via apolipoprotein-(Apo)-A1, a major component of HDL [ 55 ]. HDLs have several different roles during the acute stress response, such as promoting clearance of bacterial toxins, reducing platelet aggregation, inhibiting endothelial cell activation and apoptosis [ 113 ] and supporting the corticosteroid stress response [ 56 ]. Reduced levels of HDL, LDL and Apo-A1 were consistently reported in non-survivors in comparison to survivors of sepsis [ 89 , 97 , 98 ], which could lead to worse outcomes through many of the mechanisms described above, but specifically, the inability to clear lps may lead to acute lung and kidney injury [ 114 ].…”

HDL and persistent inflammation immunosuppression and catabolism syndrome

“…HDL exhibits pleiotropic effects during the acute inflammatory response, including clearing bacterial toxins, supporting corticosteroid release, decreasing platelet aggregation, inhibiting endothelial cell apoptosis, reducing the monocyte inflammatory response and inhibiting expression of endothelial cell adhesion molecules [4]. In severe sepsis, serum cholesterol levels drop nearly 50% [5].…”