The Fitzgerald Laboratory explores the molecular mechanisms that cells use to export cholesterol and phospholipid to extracellular acceptor proteins, a process termed lipid efflux. We study ABCA1, a transporter that binds apolipoprotein A-I, and transfers cholesterol and phospholipids onto it.

The physiologic importance of this activity is clear since mutations in ABCA1 cause Tangier disease, a rare genetic syndrome characterized by a lack of circulating HDL (“good cholesterol”), a massive build-up of cholesterol in the peripheral tissues and a elevated risk of cardiovascular disease. ABCA1 polymorphisms further associate with HDL levels and cardiovascular disease in the general population suggesting therapeutic activation of ABCA1 may reduce atherosclerotic vascular disease.

We develop proteomic and functional screens to identify cellular proteins that bind ABCA1 and modulate its efflux function. Using affinity purification, mass spectrometry and protein arrays these screens have identified classes of factors that respectively stimulate and inhibit ABCA1 activity. Typifying the positive acting factors is the interaction of ABCA1 with β1-syntrophin, a PDZ protein that organizes multiprotein complexes. β1-syntrophin binds a conserved motif in the C-terminus of ABCA1 increasing efflux and ABCA1 expression at the cell surface.

Conversely, SPTLC1, a subunit of the enzyme that controls de novo synthesis of sphingolipids, including the phospholipid sphingomyelin, binds ABCA1 and blocks its exit from the endoplasmic reticulum, thereby reducing its lipid efflux activity. Our results suggest the hypothesis that the cell has evolved a network of protein-protein interactions that act as homeostatic regulators to balance cellular lipid efflux versus de novo membrane synthesis.

Ongoing work aims to test this hypothesis at the biochemical, cellular and in vivo levels.