The Interleukine-6 (IL-6) and IL-8 response seem to be impaired upon lipopolysaccharide (LPS) stimulation in patients with long-chain fatty acid oxidation disorder (LCFAOD), according to a new study presented at the 2023 lecture series of the International Network for Fatty Acid Oxidation Research and Management (INFORM).

The aim of the researchers was to investigate whether the immune response is dysregulated in dermal fibroblasts from patients with LCFAOD when stimulated with inflammatory signals. This could help us understand whether inflammatory dysfunction could be a driver in the pathophysiology of the disease and If so, whether it could 1 day be used as a therapeutic target. 

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The researchers analyzed fibroblasts derived from 2 patients with multiple acyl-CoA dehydrogenation deficiency (MADD) and 6 patients with very-long-chain acyl-coenzyme A (CoA) dehydrogenase deficiency (VLCADD).

They first confirmed disease severity in these patients by measuring the fatty acid oxidation flux and showed that the 2 patients with MADD had almost no palmitate flux and the patients with mild VLCADD had somewhat normal oleate oxidation flux while for those with severe disease this was significantly decreased. 

They then incubated the fibroblasts from both types of patients with LPS, a simulation of a bacterial infection, and showed that there was no IL-6 response. Similar results were seen with the IL-8 response. 

Notably, when they simulated a viral infection instead of a bacterial infection, the researchers saw a perfect IL-6 response in all cell lines.  

The study authors also showed that LPS receptors were downregulated but only at the mRNA levels and not at the protein level.

Metabolomic analysis showed that LPS stimulation led to the upregulation of many essential and nonessential amino acids in patient samples, especially in those with VLCADD.

Finally, the researchers showed that inhibiting mTOR signaling could restore IL-6 response, suggesting that it may play a role in cytokine response. However, this response was not further increased upon LPS stimulation, suggesting that mTOR is not the only player in the process. 

More research is needed to better understand the mechanism of the impaired cytokine response in LCFAOD, they concluded.


Mosegaard S. Impaired cytokine production upon LPS stimulation in long-chain fatty acid oxidation disorders. Lecture presented at the International Network for Fatty Acid Oxidation Research and Management (INFORM) 2023 lecture series: April 17, 2023; Virtual.