|
RESEARCH SUMMARY: Our laboratory is interested in sterol homeostasis and in the molecular mechanisms involved in the conversion of macrophages into foam cells. This latter process is particularly relevant in several human pathologies, including atherosclerosis and different pulmonary lipidosis syndromes.
Unesterified cholesterol has very potent cytotoxic effects. Consequently, cells have evolved different mechanisms to protect themselves from cholesterol “poisoning”. ABCG1 is a transmembrane transporter that is highly induced following treatment of macrophages with oxidized or acetylated LDL (low-density lipoprotein). Although the real substrate of ABCG1 remains still a mystery, it is well established that this transporter facilitates removal of intracellular cholesterol to specific extracellular acceptors, such as HDL (high-density lipoprotein). We have access to mice deficient in ABCG1. These mice show a severe pulmonary phenotype that involves deposition of cholesterol and phospholipids in alveolar macrophages and in epithelial type 2 cells, paralleled by a dramatic inflammatory process. Interestingly, this phenotype unfolds in the absence of changes in plasma lipids. Perhaps not surprisingly, lack of removal of intracellular sterols in Abcg1-/- cells also results in increased susceptibility to apoptosis.
We are currently expanding our analysis of the lungs of the Abcg1-/- mice, focusing on the cross-talk between alveolar macrophages and other cells types. We are also interested in understanding how deregulation of sterol homeostasis leads to pulmonary inflammation.
Finally, we are developing high-throughput screening assays to discover new genes and pathways involved in foam cell formation in macrophages in the artery wall, and how these new genes impact the development of lesions in mouse models of atherosclerosis such as Ldlr-/- and ApoE-/-. |
