Summary
A bioRxiv preprint links neutrophil alpha-defensins to mitochondrial changes and fat accumulation in liver cells. The proposed pathway is supported by cell experiments and a mouse model, while the patient findings are correlational.
A bioRxiv preprint reports that human neutrophil peptides, also called alpha-defensins, may help drive metabolic dysfunction-associated steatotic liver disease (MASLD) by disrupting a mitochondrial protein in liver cells. The authors connect findings from a patient cohort with laboratory experiments and a mouse model; the preprint has not been peer reviewed.
The proposed immune-to-mitochondria pathway
Neutrophils are immune cells that release human neutrophil peptides (HNPs) as part of the body’s defence response. The study reports that HNPs can enter hepatocytes, the main cells of the liver, and promote the assembly of voltage-dependent anion channel 1 (VDAC1) into larger complexes in the mitochondria’s outer membrane.
Mitochondria help cells produce energy and regulate other cellular processes. In experiments with hepatocytes, the researchers found that HNP exposure was followed by mitochondrial dysfunction and lipid accumulation. This suggests a route by which an immune response could contribute to fat build-up in liver cells, rather than simply accompanying disease progression.
Evidence from patients, cells and mice
In a clinical cohort of people with MASLD, the amount of HNP found in diseased liver tissue correlated with the histological severity of steatosis, or fat accumulation. This patient finding is an association. The cell experiments provide evidence for a possible mechanism, while the mouse experiments tested the pathway in an animal model.
Mice engineered to produce HNP1 developed greater adiposity and steatohepatitis under lipid overload, but not when fed a standard diet. The authors also report that an orally available prodrug that inhibits HNP-induced VDAC1 multimerization reversed the effects in the mice. The preprint therefore identifies the HNP–VDAC1 pathway as a potential therapeutic target, but the intervention evidence described is preclinical; whether it can be safe and effective in people remains to be tested.