Transport of lipids from Golgi to plasma membrane is defective in Tangier disease patients and Abc1-deficient mice

Abstract

Mutations in the gene encoding ATP-binding cassette transporter 1 ( ABC1) have been reported in Tangier disease (TD), an autosomal recessive disorder that is characterized by almost complete absence of plasma high-density lipoprotein (HDL), deposition of cholesteryl esters in the reticulo-endothelial system (RES) and aberrant cellular lipid trafficking. We demonstrate here that mice with a targeted inactivation of Abc1 display morphologic abnormalities and perturbations in their lipoprotein metabolism concordant with TD. ABC1 is expressed on the plasma membrane and the Golgi complex, mediates apo-AI associated export of cholesterol and phospholipids from the cell, and is regulated by cholesterol flux. Structural and functional abnormalities in caveolar processing and the trans-Golgi secretory pathway of cells lacking functional ABC1 indicate that lipid export processes involving vesicular budding between the Golgi and the plasma membrane are severely disturbed.

Enlargement of High Density Lipoprotein in Mice via Liver X Receptor Activation Requires Apolipoprotein E and Is Abolished by Cholesteryl Ester Transfer Protein Expression

“…ABCA1 deficiency leads to a near total absence of HDL cholesterol both in humans and mice (22)(23)(24)(25)(26)(27). The molecular mechanisms of ABCA1 contributing to the HDL biogenesis, however, may need further refinement.…”

“…The enlargement of HDL after LXR agonist administration to mice may largely involve the induction of ABCA1 and apoE, since both gene products are intimately involved in HDL metabolism and are regulated by LXRs (10,11,21). ABCA1 deficiency causes hypoalphalipoproteinemia in humans (22-25) and mice (26,27). ABCA1 overexpression in mice leads to an increased plasma HDL cholesterol level (28,29).…”

Cholesterol transporter ATP-binding cassette A1 (ABCA1) is elevated in prion disease and affects PrPC and PrPSc concentrations in cultured cells

“…S2 (available with the online version of this paper). Since ABCA1 has been reported to have a function in the transport of caveolae (Orso et al, 2000), we also monitored the levels of caveolin-1 (CAV1) in some experiments; no effect of 8-Br-cAMP treatment on CAV1 levels was found. The 8-Br-cAMP-induced elevation of ABCA1 and PrP Sc concentrations were highly correlated (r 2 50.8277, P,0.001) as shown in Fig.…”

“…In the brain, ABCA1 is expressed in neurons, astrocytes and glial cells (Fukumoto et al, 2002; Koldamova et al, 2003). ABCA1 is involved in the transport of intracellular cholesterol and caveolae from the trans-Golgi to the plasma membrane and Abca1 mutations cause Tangier disease (Lawn et al, 1999;Orso et al, 2000). The potential importance of cholesterol in prion disease has been established by the inhibitory effect of pharmacological depletion of cellular cholesterol (Bate et al, 2004;Gilch et al, 2006;Marella et al, 2002; Taraboulos et al, 1995).…”

A New N-Terminal Recognition Domain in Caveolin-1 Interacts with Sterol Carrier Protein-2 (SCP-2)

“…Once bound to SRB1, HDL cholesteryl ester is transferred to the PM lipid rafts/caveolae, internalized by an unresolved, non-endocytic process and undergoes hydrolysis by nonlysosomal, neutral esterases to free cholesterol (17,18). Third, unidirectional cholesterol efflux occurs via the ATP-binding cassette transporter A1 (ABCA1) (19)(20)(21) which localizes to lipid rafts/caveolae (22,23). ABCA1 binds apoprotein-1 (apoA1) to enhance phospholipid efflux, followed by ABCA1 independent cholesterol transfer to the phospholipid containing apoA1, which then becomes HDL (21,24) .…”