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Review
. 2022 Mar 31:13:867261.
doi: 10.3389/fimmu.2022.867261. eCollection 2022.

Lipids in Liver Failure Syndromes: A Focus on Eicosanoids, Specialized Pro-Resolving Lipid Mediators and Lysophospholipids

Florent Artru  1 , Mark J W McPhail  1 , Evangelos Triantafyllou  2 , Francesca Maria Trovato  1
Affiliations
Review

Lipids in Liver Failure Syndromes: A Focus on Eicosanoids, Specialized Pro-Resolving Lipid Mediators and Lysophospholipids

Florent Artru et al. Front Immunol. .

Abstract

Lipids are organic compounds insoluble in water with a variety of metabolic and non-metabolic functions. They not only represent an efficient energy substrate but can also act as key inflammatory and anti-inflammatory molecules as part of a network of soluble mediators at the interface of metabolism and the immune system. The role of endogenous bioactive lipid mediators has been demonstrated in several inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, cancer). The liver is unique in providing balanced immunotolerance to the exposure of bacterial components from the gut transiting through the portal vein and the lymphatic system. This balance is abruptly deranged in liver failure syndromes such as acute liver failure and acute-on-chronic liver failure. In these syndromes, researchers have recently focused on bioactive lipid mediators by global metabonomic profiling and uncovered the pivotal role of these mediators in the immune dysfunction observed in liver failure syndromes explaining the high occurrence of sepsis and subsequent organ failure. Among endogenous bioactive lipids, the mechanistic actions of three classes (eicosanoids, pro-resolving lipid mediators and lysophospholipids) in the pathophysiological modulation of liver failure syndromes will be the topic of this narrative review. Furthermore, the therapeutic potential of lipid-immune pathways will be described.

Keywords: acute liver failure; acute on chronic liver failure; cirrhosis; lipids; liver; liver failure; metabonome; systems biology.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic illustration of the different pathways of eicosanoids, specialized pro-resolving mediators (SPMs) and lysophospholipids metabolism. Eicosanoid’s mediators are in red, SPMs mediators in green and lysophospholipids mediators in blue. Enzymes are in round grey areas, common receptors in rectangular grey areas and alternative receptors in rectangular orange areas. ATX, autotaxin; BLT, leukotriene receptor, C1P, ceramide-1-phosphate; CERS, ceramide synthases; COX, cyclooxygenase; PLA2, phospholipase A2; CYP, cytochrome P450; CysLTs, cysteinyl leukotrienes; CysLTR, cysteinyl leukotrienes receptors; DHA, docosahexaenoic acid; DP, prostaglandin D receptor; DPA, docosapentaenoic acid; EET, epoxyeicosatetraenoic acid; EP, prostaglandin E receptor; EPA, eicosapentaenoic acid; ERV, E-series resolvin receptor; FA, fatty acid; FLAP, 5-LOX activating protein; FP, prostaglandin F receptor; GPR, G protein-coupled receptor; HETE, hydroxy eicosatetraenoic acid; HpETE, hydroperoxy eicosatetraenoic acid; Hx, hepoxilin; IP, prostacyclin receptor; LGR6, leucine-rich repeat containing G protein-coupled receptor 6; LTB4, leukotriene B4; LOX, lipoxygenase; LPA, lysophosphatidic acid; LPAR, lysophosphatidic acid receptor; LPC, lysophosphatidylcholine; LPSe, lysophosphatidylserine; LPI, lysophosphatidylinositol; LX, lipoxin; MaR, maresin; MCTR1, maresin conjugates in tissue regeneration 1; PCTR, protectin conjugates in tissue regeneration; PD, protectins; PG, prostaglandin; PGS, prostaglandin synthase; PPAR, peroxisome proliferator-activated receptor; RvD, D-series resolvin; RvE, E-series resolvin; RvT, thirteen-series resolvin; S1P, Sphingosine-1-phosphate; S1PR, Sphingosine-1-phosphate receptor; SM, sphingomyelinase; SPMs, specialized pro-resolving mediator; SPT, serine -palmitoyl transferase; TRPV, transient receptor potential vanilloide 1; TP, thromboxane receptor; Tx, thromboxane; TXAS, TxA synthase.
Figure 2
Figure 2
Schematic illustration of the pathophysiology of acute liver failure (ALF- left panel) and acute on chronic liver failure (ACLF - right panel). The main endogenous bioactive lipids are identified with colours: eicosanoids in red, specialized pro-resolving lipid mediators (SPMs) in green, lysophospholipids in blue. Reported effects of the underlined mediators illustrate only investigation in sepsis models. Left panel: ALF starts with an acute liver insult (viral, toxic, ischemia, traumatism) occurring on a healthy liver leading to the release of danger-associated molecular patterns (DAMPS), inflammasome activation and secretion of pro-inflammatory cytokines and chemokines, coagulation activation and mitochondrial dysfunction leading to the release of reactive oxygen species (ROS). In ALF, a global increase in eicosanoids mediators and ceramide has been reported while the global trend of SPMs level is not known. The consequences are mainly those of perpetuating hepatocytes damages (cell death by necrosis, apoptosis, defect in liver regeneration aggravated by resident macrophages activation) and activation of circulating immune compartment through a pro-inflammatory phenotype (bacterial killing with phagocytosis, secretion of pro-inflammatory signals favouring leukocytes recruitment and tissue infiltration). A switch to a pro-restorative phenotype (decreased bacterial killing capacity and phagocytosis, increased efferocytosis function) occurs during the disease course exposing leading to systemic immunosuppression. All together these mechanisms lead to severe systemic inflammation and when uncontrolled infection, multi-organ failures and death. The effect investigated in experimental and translational studies of each lipid mediator is reported. (+) or (-) corresponds to its action on the pathophysiologic step (e.g., PGE1 decreases the hepatocytes damages in experimental models of ALF). Right panel: ACLF starts with a precipitating event (e.g., alcoholic hepatitis, infection, drug-induced liver injury, hepatitis B reactivation, gastrointestinal bleeding), occurring on a chronically affected liver. This leads to an increase in bacterial translocation, mitochondrial dysfunction with the generation of ROS and pro-inflammatory oxidized form of albumin, inflammasome activation and secretion of pro-inflammatory cytokines and chemokines. In ACLF, a global increase in eicosanoids mediators and LPA and a decrease in SPMs and LPC levels has been reported. The consequences are mainly a release of pathogen-associated molecular patterns (PAMPs) and DAMPs leading to intense systemic inflammation. The circulating immune compartment can be either pro-inflammatory or pro-restorative favouring infection, organ failures and death. As for the left panel, the effect investigated in experimental and translational studies of each lipid mediator is reported. (+) or (-) corresponds to its action on the pathophysiologic step (e.g., PGE2 favours the pro-restorative phenotype of the immune cell compartment). The bottom of the figure reports the different molecules that were clinically shown to modulate the action of the lipid mediator reported in the left and right panels. ATX, autotaxin, C1P, ceramide-1-phosphate; COX, cyclooxygenase; CysLTs, cysteinyl leukotrienes; DAMPs, danger-associated molecular patterns; FLAP, 5-LOX activating protein; LTB4, leukotriene B4; LOX, lipoxygenase; LPA, lysophosphatidic acid; LPAR, lysophosphatidic acid receptor; LPC, lysophosphatidylcholine; LX, lipoxin; MaR, maresin; MCTR1, maresin conjugates in tissue regeneration 1; PAMPs, pathogen-associated molecular patterns; PG, prostaglandin; RvD, D-series resolvin; RvE, E-series resolvin; S1P, Sphingosine-1-phosphate; S1PR, Sphingosine-1-phosphate receptor; SPMs, specialized pro-resolving mediator.
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