AOAH-mediated LPS inactivation limits macrophage endotoxin tolerance and promotes inflammation and fibrosis in MASH

Chronic liver diseases such as metabolic dysfunction-associated steatohepatitis (MASH) involve persistent low-grade inflammation, partly driven by low levels of gut-derived lipopolysaccharide (LPS). While repeated LPS exposure can induce endotoxin tolerance in innate immune cells, its role in chronic liver diseases remains unclear. Acyloxyacyl hydrolase (AOAH) is endogenous enzyme that inactivates LPS, potentially modulating this process. We investigated how AOAH regulates endotoxin tolerance in Kupffer cells (KCs) and assess its impact on hepatic inflammation and fibrosis in MASH. LPS-preconditioned KCs exhibited reduced pro-inflammatory cytokine production and transcriptional suppression of inflammatory pathways, indicating tolerance. Despite slight elevation of plasma LPS levels in MASH, upregulation of hepatic AOAH positively correlated with disease severity, suggesting enhanced LPS inactivation but impaired establishment of tolerance. In contrast, AOAH-deficient KCs displayed reinforced endotoxin tolerance, leading to diminished hepatic inflammation and fibrosis. Reversal of tolerance using β-glucan reactivated inflammatory and fibrogenic responses in AOAH-deficient mice, whereas tolerance induction by low-dose LPS preconditioning mitigated MASH pathology, supporting the protective role of macrophage tolerance in chronic liver injury. Endotoxin tolerance in KCs represents a protective mechanism against chronic liver inflammation and fibrosis. AOAH regulates this state by limiting bioactive LPS. Enhancing macrophage tolerance by utilizing LPS may offer a novel therapeutic avenue to control the progression of MASH.