Human inborn errors of long‐chain fatty acid oxidation show impaired inflammatory responses to TLR4‐ligand LPS

Stimulation of mammalian cells with inflammatory inducers such as lipopolysaccharide (LPS) leads to alterations in activity of central cellular metabolic pathways. Interestingly, these metabolic changes seem to be important for subsequent release of pro‐inflammatory cytokines. This has become particularly clear for enzymes of tricarboxylic acid (TCA) cycle such as succinate dehydrogenase (SDH). LPS leads to inhibition of SDH activity and accumulation of succinate to enhance the LPS‐induced formation of IL‐1β. If enzymes involved in beta‐oxidation of fatty acids are important for sufficient responses to LPS is currently not clear. Using cells from various patients with inborn long‐chain fatty acid oxidation disorders (lcFAOD), we report that disease‐causing deleterious variants of Electron Transfer Flavoprotein Dehydrogenase (ETFDH) and of Very Long Chain Acyl‐CoA Dehydrogenase (ACADVL), both cause insufficient inflammatory responses to stimulation with LPS. The insufficiencies included reduced TLR4 expression levels, impaired TLR4 signaling, and reduced or absent induction of pro‐inflammatory cytokines such as IL‐6. The insufficient responses to LPS were reproduced in cells from healthy controls by targeted loss‐of‐function of either ETFDH or ACADVL, supporting that the deleterious ETFDH and ACADVL variants cause the attenuated responses to LPS. ETFDH and ACADVL encode two distinct enzymes both involved in fatty acid beta‐oxidation, and patients with these deficiencies cannot sufficiently metabolize long‐chain fatty acids. We report that genes important for beta‐oxidation of long‐chain fatty acids are also important for inflammatory responses to an acute immunogen trigger like LPS, which may have important implications for understanding infection and other metabolic stress induced disease pathology in lcFAODs. We report that inactivating gene variants of Electron Transfer Flavoprotein Dehydrogenase (ETFDH) or Very Long Chain Acyl‐CoA Dehydrogenase (ACADVL) caused insufficient responses to Lipopolysaccharide (LPS) which was also mimicked in cells from normal healthy controls under targeted loss‐of‐function of same genes. It included impaired TLR4 signaling and reduced or absent induction of pro‐inflammatory cytokines like IL‐6. This links inborn errors in long‐chain fatty acid oxidation (lcFAOD) to insufficient responses to LPS, which may have important implications for understanding infection‐induced disease pathology in lcFAODs.