Lipid hormones and atherosclerosis

Recent studies have shown that the bioactive lipid species, lipokines, released by adipose tissues can profoundly affect metabolism. Lipokines are a lipid-controlling hormone. The lipokine PAO travels to the muscles and liver, where it improves cell sensitivity to insulin and blocks fat accumulation in the liver. Researchers have observed that PAO suppresses inflammation, which is considered a primary factor leading to metabolic disease.

The EU-funded project LIPOKINES (The impact of bioactive lipokines on atherosclerosis) investigated the potential of PAO for nutritional modification of the cross-talk between metabolism, inflammation and stress pathways in atherosclerosis.

Promising results showed that in vivo PAO nutritional treatment could significantly reduce atherosclerotic lesions. In parallel, in vitro studies revealed that PAO has a significant anti-inflammatory effect in macrophages, including suppression of inflammatory cytokine (inflammasome) production.

Researching into how PAO can bring about these beneficial changes, the scientists found that PAO can block lipid-induced (palmitate or PA) endoplasmic reticulum (ER) stress, lesion ER stress and apoptosis. Moreover, when chronic PAO treatment blocks inflammasome activity, this results in reduced secretion of Interleukin-1 beta in serum that causes autoinflammatory diseases.

PAO also blocks palmitic acid-induced generation of reactive oxygen species from the mitochondria in both primary bone marrow derived macrophages and human THP1 cells as well as in vascular smooth muscle. Reduction in foam cells in atherosclerotic plaques from PAO-treated mice appear to be due to either reduced number of macrophages in lesions or decreased lipid accumulation in other cell types that occur in the plaques.

Researchers also carried out a lipidomic analysis in macrophages with elevated PAO production to analyse the distribution of the newly synthesised PAO in the lipid classes. One of the main destinations was the phospholipid class. More interesting still, PAO's action and incorporation into cardiolipin suggests actual remodelling of the inner membrane of the mitochondrion. This would have a significant impact on mitochondrial stress responses.Metabolic inflammation is a major contributor to many chronic diseases including obesity, atherosclerosis, diabetes, cancer, neurodegenerative diseases and ageing. The results of the LIPOKINES project are therefore expected to have a multidisciplinary impact.