Acute-on-chronic liver failure (ACLF) is a complex syndrome that develops in patients with cirrhosis and is characterized by acute decompensation, organ failure(s) and high short-term mortality. ACLF frequently occurs in close temporal relationship to a precipitating event, such as acute alcoholic, drug-induced or viral hepatitis or bacterial infection and, in cases without precipitating events, probably related to intestinal translocation of bacterial products. Dysbalanced immune function is central to its pathogenesis and outcome with an initial excessive systemic inflammatory response that drives organ failure and mortality. This hyperinflammatory state ultimately impairs the host defensive mechanisms of immune cells, rendering ACLF patients immunocompromised and more vulnerable to secondary infections, and therefore to higher organ dysfunction and mortality. In this review, we describe the prevailing characteristics of the hyperinflammatory state in patients with acutely decompensated cirrhosis developing ACLF, with special emphasis on cells of the innate immune system (i.e., monocytes and neutrophils), their triggers (pathogen- and damage-associated molecular patterns [PAMPs and DAMPs]), their effector molecules (cytokines, chemokines, growth factors and bioactive lipid mediators) and the consequences on tissue immunopathology. In addition, this review includes a chapter discussing new emerging therapies based on the modulation of leukocyte function by the administration of pleiotropic proteins such as albumin, Toll-like receptor 4 antagonists, interleukin-22 or stem cell therapy. Finally, the importance of finding an appropriate intervention that reduces inflammation without inducing immunosuppression is highlighted as one of the main therapeutic challenges in cirrhosis.

Soluble guanylate cyclase (sGC) catalyzes the conversion of guanosine triphosphate into cyclic guanosine-3′,5′-monophosphate, a key second messenger in cell signaling and tissue homeostasis. It was recently demonstrated that sGC stimulation is associated with a marked antiinflammatory effect in the liver of mice with experimental nonalcoholic steatohepatitis (NASH). Here, we investigated the mechanisms underlying the antiinflammatory effect of the sGC stimulator praliciguat (PRL) in the liver. Therapeutic administration of PRL exerted antiinflammatory and antifibrotic actions in mice with choline-deficient l-amino acid-defined high-fat diet-induced NASH. The PRL antiinflammatory effect was associated with lower F4/80- and CX3CR1-positive macrophage infiltration into the liver in parallel with lower Ly6C^High- and higher Ly6C^Low-expressing monocytes in peripheral circulation. The PRL antiinflammatory effect was also associated with suppression of hepatic levels of interleukin (IL)-1β, NLPR3 (NACHT, LRR, and PYD domain-containing protein 3), ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain), and active cleaved-caspase-1, which are components of the NLRP3 inflammasome. In Kupffer cells challenged with the classical inflammasome model of lipopolysaccharide plus adenosine triphosphate, PRL inhibited the priming (expression of Il1b and Nlrp3) and blocked the release of mature IL-1β. Mechanistically, PRL induced the protein kinase G (PKG)-mediated phosphorylation of the VASP (vasodilator-stimulated phosphoprotein) Ser239 residue which, in turn, reduced nuclear factor-κB (NF-κB) activity and Il1b and Nlrp3 gene transcription. PRL also reduced active cleaved-caspase-1 levels independent of pannexin-1 activity. These data indicate that sGC stimulation with PRL exerts antiinflammatory actions in the liver through mechanisms related to a PKG/VASP/NF-κB/NLRP3 inflammasome circuit. Significance Fatty liver, which is an initial step in the development of more severe complications such as liver cirrhosis, is prevalent worldwide in our society. This study demonstrates that stimulation of soluble guanylate cyclase (sGC), an enzyme producing the second messenger cGMP, protects against the most common features of fatty liver, namely inflammation and fibrosis, in animal models of the disease. Our study also provides an explanation for this protection and describes how sGC stimulation blocks the inflammasome (a protein complex responsible for the production of the potent proinflammatory cytokine interleukin-1β) in liver macrophages. The results of this study support the investigation of sGC stimulators, which are already approved for treatment in other conditions, in patients with fatty liver disease.

Specialized proresolving mediators (SPMs) biosynthesized from docosahexaenoic acids (DHAs) including resolvins (Rvs), protectins, and maresins are potent endogenous autacoids that actively resolve inflammation, protect organs, and stimulate tissue regeneration. Our hypothesis was that failure of resolution programs may lead to unremitting inflammation in obesity, contributing to the development of metabolic comorbidities in this condition. Obese individuals with persistent low‐grade systemic inflammation showed reduced leukocyte production of the DHA‐derived monohydroxy fatty acid 17—hydroxy‐DHA (HDHA) and unbalanced formation of SPMs (in particular d ‐series Rvs) accompanied by enhanced production of proinflammatory lipid mediators such as leukotriene B ₄ . Mechanistic studies attributed this impairment to reduced 15‐lipoxygenase (LOX) activity rather than altered DHA cellular uptake. Moreover, leukocytes from obese individuals exhibited decreased 5‐LOX levels and reduced 5‐LOX Ser271 phosphorylation and distinct intracellular 5‐LOX redistribution. However, 15‐LOX appears to be the most critical factor for the deficient production of SPMs by obese leukocytes because the formation of d ‐series Rvs was completely rescued by incubation with the intermediate precursor 17‐HDHA. These data provide proof of concept that administration of intermediate precursors of SPM biosynthesis ( e.g ., 17‐HDHA) could be more efficient in overriding impaired formation of these proresolving lipid mediators in conditions characterized by dysfunctional LOX activity, such as obesity.—López‐Vicario, C, Titos, E., Walker, M. E., Alcaraz‐Quiles, J., Casulleras, M., Durán‐Güell, M., Flores‐Costa, R., Pérez‐Romero, N., Forné, M., Dalli, J., Clària, J. Leukocytes from obese individuals exhibit an impaired SPM signature. FASEB J. 33, 7072–7083 (2019). www.fasebj.org

Background and Aim: Injury to hepatocyte mitochondria is common in metabolic dysfunction‐associated fatty liver disease. Here, we investigated whether changes in the content of essential fatty acid–derived lipid autacoids affect hepatocyte mitochondrial bioenergetics and metabolic efficiency. Approach and Results: The study was performed in transgenic mice for the fat‐1 gene, which allows the endogenous replacement of the membrane omega‐6–polyunsaturated fatty acid (PUFA) composition by omega‐3–PUFA. Transmission electron microscopy revealed that hepatocyte mitochondria of fat‐1 mice had more abundant intact cristae and higher mitochondrial aspect ratio. Fat‐1 mice had increased expression of oxidative phosphorylation complexes I and II and translocases of both inner (translocase of inner mitochondrial membrane 44) and outer (translocase of the outer membrane 20) mitochondrial membranes. Fat‐1 mice also showed increased mitofusin‐2 and reduced dynamin‐like protein 1 phosphorylation, which mediate mitochondrial fusion and fission, respectively. Mitochondria of fat‐1 mice exhibited enhanced oxygen consumption rate, fatty acid β‐oxidation, and energy substrate utilization as determined by high‐resolution respirometry, [1‐¹⁴C]‐oleate oxidation and nicotinamide adenine dinucleotide hydride/dihydroflavine‐adenine dinucleotide production, respectively. Untargeted lipidomics identified a rich hepatic omega‐3–PUFA composition and a specific docosahexaenoic acid (DHA)–enriched lipid fingerprint in fat‐1 mice. Targeted lipidomics uncovered a higher content of DHA‐derived lipid autacoids, namely resolvin D1 and maresin 1, which rescued hepatocytes from TNFα‐induced mitochondrial dysfunction, and unblocked the tricarboxylic acid cycle flux and metabolic utilization of long‐chain acyl‐carnitines, amino acids, and carbohydrates. Importantly, fat‐1 mice were protected against mitochondrial injury induced by obesogenic and fibrogenic insults. Conclusion: Our data uncover the importance of a lipid membrane composition rich in DHA and its lipid autacoid derivatives to have optimal hepatic mitochondrial and metabolic efficiency.

Inflammation is a characteristic feature of virtually all acute and chronic liver diseases. It intersects different liver pathologies from the early stages of liver injury, when the inflammatory burden is mild-to-moderate, to very advanced stages of liver disease, when the inflammatory response is very intense and drives multiple organ dysfunction and failure(s). The current review describes the most relevant features of the inflammatory process in two different clinical entities across the liver disease spectrum, namely non-alcoholic steatohepatitis (NASH) and acute-on-chronic liver failure (ACLF). Special emphasis is given within these two disease conditions to gather the most relevant data on the specialized pro-resolving mediators that orchestrate the resolution of inflammation, a tightly controlled process which dysregulation commonly associates with chronic inflammatory conditions.

In patients with cirrhosis, acute decompensation (AD) correlates with a hyperinflammatory state driven by mitochondrial dysfunction, which is a significant factor in the progression toward acute-on-chronic liver failure (ACLF). Elevated circulating levels of acylcarnitine, indicative of mitochondrial dysfunction, are predictors of mortality in ACLF patients. Our hypothesis posits that acylcarnitines not only act as biomarkers, but also actively exert detrimental effects on circulating immune cells. Plasma acylcarnitine levels were measured in 20 patients with AD cirrhosis and 10 healthy individuals. The effects of selected medium- and long-chain acylcarnitines on mitochondrial function were investigated in peripheral leucocytes from healthy donors by determining mitochondrial membrane potential (Δψm) and mitochondrial respiration using the JC-1 dye and Agilent Seahorse XF technology. Changes regarding mitochondrial ultrastructure and redox systems were assessed by transmission electron microscopy and gene and protein expression analysis. Plasma levels of several acylcarnitine species were significantly elevated in patients with AD cirrhosis compared with healthy individuals, alongside increased levels of inflammatory mediators (cytokines and chemokines). Notably, the long-chain acylcarnitine palmitoylcarnitine (C16:0-carnitine, 1.51-fold higher, p = 0.0059) impaired Δψm and reduced the spare respiratory capacity of peripheral mononuclear leucocytes. Additionally, C16:0-carnitine induced mitochondrial oxidative stress, suppressed the expression of the antioxidant gene HMOX1, and increased CXCL8 expression and IL-8 release. Etomoxir, which blocks acylcarnitine entry into the mitochondria, reversed the suppression of HMOX1. Similarly, trimetazidine, a fatty acid beta-oxidation inhibitor, prevented C16:0-carnitine-induced CXCL8 expression. Importantly, oxidative stress and Δψm impairment caused by C16:0-carnitine were less severe in the presence of albumin, a standard therapy for AD cirrhosis. Our findings suggest that long-chain acylcarnitines induce mitochondrial injury in immune cells, thereby contributing to the development of immune dysfunction associated with cirrhosis. Patients with acute decompensation of cirrhosis and acute-on-chronic liver failure (ACLF) display a systemic hyperinflammatory state and leukocyte mitochondrial dysfunction. We discovered that apart from being increased in the circulation of these patients, the long-chain palmitoylcarnitine is able to elicit cytokine secretion paired with mitochondrial dysfunction in leukocytes from healthy donors. In particular, we show that inhibiting the metabolism of palmitoylcarnitine could reverse these detrimental effects. Our findings underline the importance of immunometabolism as a treatment target in patients with acute decompensation of cirrhosis and ACLF.