Cholesterol efflux is promising therapeutic target in AMD
medwireNews: Abnormal cholesterol metabolism in the eye is involved in the pathogenesis of age-related macular degeneration (AMD), a study in mice has shown.
The research also found that this process could be reversed through liver X receptor (LXR) agonism, raising the possibility of a new therapeutic option for AMD and related diseases.
"This study points to a novel strategy for early intervention to prevent the progression of AMD to the severe neovascular form of the disease," said Grace Shen, from the National Eye Institute, Bethesda, Maryland, USA, which funded the research.
In a series of experiments, Rajendra Apte (Washington University School of Medicine, Saint Louis, Missouri, USA) and team investigated the potential link between abnormal lipid regulation in the senescent macrophage and its effects on inflammation-driven angiogenesis in age-associated eye disease.
They began by studying in vitro macrophages from young (<3 months) and old (>18 months) mice. They found that aging was associated with reduced expression of ATP binding cassette (ABC) transporters, which impaired the macrophages' ability to efflux cholesterol effectively. This in turn led to higher levels of free cholesterol within the cells.
Further, the researchers showed that senescent macrophages were alternatively (as opposed to classically) activated, produced anti-inflammatory cytokines, and were abnormally polarized.
"Elevated intracellular lipid polarizes older macrophages to an abnormal, alternatively activated phenotype that promotes pathologic vascular proliferation," they write in Cell Metabolism.
Next the team studied mice deficient for Abca1, which had an accelerated aging phenotype. They found that local or systemic administration of a synthetic LXR agonist caused macrophage efflux to be restored to levels seen in young macrophages.
The same effect was obtained when macrophages were transfected with an inhibitor of miR-33, a highly conserved microRNA that regulates the expression of genes involved in cellular cholesterol metabolism.
Finally, in vitro analysis of monocytes from human patients with neovascular AMD showed that ABCA1 expression was significantly lower in cells from older versus younger individuals.
Noting that their results "have significant therapeutic implications," the researchers conclude: "Therapeutic intervention prior to the development of advanced disease with effective agents that upregulate macrophage cholesterol efflux in the eye might prevent progression and can be used as prophylaxis against the development of choroidal neovascularization and its blinding complications."
medwireNews (www.medwirenews.com) is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2013
By Joanna Lyford, Senior medwireNews Reporter