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PubMed1992

Neutrophil activation associated with increased neutrophil acyloxyacyl hydrolase activity during inflammation in cattle.

Acyloxyacyl hydrolase (AOAH) is a lysosomal enzyme found in neutrophils and macrophages that acts to partially deacylate the lipid-A component of the endotoxin of gram-negative bacteria rendering it less toxic, yet maintaining much of its immunostimulatory potential. We have found that the activity of neutrophil AOAH per cell increased during localized inflammation. The purpose of this study was to determine the mechanism(s) responsible for these increases in neutrophil AOAH activity. Because changes in neutrophil maturity commonly are associated with inflammation, intravascular infusion of purified gram-negative bacterial lipopolysaccharide and SC injection of bovine recombinant granulocyte colony-stimulating factor was used to induce large numbers of circulating immature neutrophils. Immature neutrophils were found to have AOAH activity equal to that of mature cells; however, when neutrophils were stimulated in vitro with known activators, AOAH activity of activated cells was more than that of unstimulated cells. The increase in AOAH activity was inversely related to prestimulation activity. Increases in AOAH activity after neutrophil activation were not a result of de novo synthesis of the enzyme, because cycloheximide did not prevent activation-induced increases in activity.

Animals↗

PubMed1992

Acyloxyacyl hydrolase, a leukocyte enzyme that deacylates bacterial lipopolysaccharides, has phospholipase, lysophospholipase, diacylglycerollipase, and acyltransferase activities in vitro.

Human acyloxyacyl hydrolase (AOAH) is a leukocyte enzyme that hydrolyzes acyloxyacyl bonds in the lipid A region of bacterial lipopolysaccharide (LPS), thereby detoxifying the LPS. We report here that the enzyme also acts in vitro on glycerophospholipids, lysophospholipids, and diacylglycerol. While AOAH preferentially removes palmitate or stearate from the sn-1 position of phospholipid and diacylglycerol substrates that have unsaturated acyl chains in the sn-2 position, it is able to cleave both palmitates from sn-1,2-dipalmitoylphosphatidylcholine and sn-1,2-dipalmitoylglycerol. This apparent preference for removing saturated (or shorter) acyl chains from glycerolipids is consistent with its ability to cleave laurate more rapidly than palmitoleate from lipopolysaccharide (Erwin, A. L., and Munford, R. S. (1990) J. Biol. Chem. 265, 16444-16449). AOAH also catalyzes acyl transfer from LPS and phosphatidylethanolamine to acceptor lipids; approximately equal amounts of laurate and myristate are transferred from LPS to monooleoylglyceryl ether, forming acyloleoylglyceryl ether. The demonstration that AOAH has phospholipase, lysophospholipase, diacylglycerol lipase, and acyltransferase activities in vitro suggests that the enzyme may have roles in addition to LPS deacylation (detoxification) in phagocytic cells.

Acyltransferases↗

PubMed2026

Acyloxyacyl Hydrolase-Mediated Lipopolysaccharide Inactivation Limits Macrophage Endotoxin Tolerance and Promotes Inflammation and Fibrosis in Metabolic Dysfunction-Associated Steatohepatitis.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis, a chronic liver disease, is characterized by persistent low-grade inflammation, partially driven by gut-derived lipopolysaccharide. Although repeated lipopolysaccharide exposure can induce endotoxin tolerance in innate immune cells, its role in chronic liver diseases remains unclear. Acyloxyacyl hydrolase is an endogenous enzyme that inactivates lipopolysaccharide, potentially modulating this process. We aimed to investigate how acyloxyacyl hydrolase regulates endotoxin tolerance in Kupffer cells and how this affects hepatic inflammation and fibrosis during metabolic dysfunction-associated steatohepatitis progression. METHODS: Acyloxyacyl hydrolase-deficient mice and wild-type controls were subjected to multiple dietary metabolic dysfunction-associated steatohepatitis models. Inflammatory responses, fibrosis, and transcriptomic changes in liver tissues and isolated Kupffer cells were analyzed. Endotoxin tolerance was modulated through β-glucan administration or lipopolysaccharide preconditioning. Lipopolysaccharide bioactivity was assessed using Toll-like receptor 4-reporter cell assays. RESULTS: Lipopolysaccharide-preconditioned Kupffer cells exhibited reduced proinflammatory cytokine production and transcriptional suppression of inflammatory pathways, indicating tolerance. Despite slight elevation of plasma lipopolysaccharide levels in metabolic dysfunction-associated steatohepatitis, upregulation of hepatic acyloxyacyl hydrolase positively correlated with disease severity, suggesting enhanced lipopolysaccharide inactivation but impaired establishment of tolerance. In contrast, acyloxyacyl hydrolase-deficient Kupffer cells displayed reinforced endotoxin tolerance, leading to diminished hepatic inflammation and fibrosis. Reversal of tolerance using β-glucan reactivated inflammatory and fibrogenic responses in acyloxyacyl hydrolase-deficient mice, whereas tolerance induction by low-dose lipopolysaccharide preconditioning mitigated metabolic dysfunction-associated steatohepatitis pathology, supporting the protective role of macrophage tolerance in chronic liver injury. CONCLUSIONS: Endotoxin tolerance in Kupffer cells represents a protective mechanism against chronic liver inflammation and fibrosis. Acyloxyacyl hydrolase regulates this state by limiting bioactive lipopolysaccharide, thereby modulating the establishment of endotoxin tolerance and downstream inflammatory and fibrotic responses. Enhancing macrophage tolerance by utilizing lipopolysaccharide may offer a novel therapeutic avenue to control the progression of metabolic dysfunction-associated steatohepatitis.

AOAH↗