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

Mutations in the gene encoding ATP-binding cassette transporter 1 (ABC1) ha ve been reported in Tangier disease(1-3) (TD), an autosomal recessive disor der that is characterized by almost complete absence of plasma high-density lipoprotein (HDL), deposition of cholesteryl esters in the reticulo-endoth elial system(4) (RES) and aberrant cellular lipid trafficking(5-12). We dem onstrate here that mice with a targeted inactivation of Abc1 display morpho logic abnormalities and perturbations in their lipoprotein metabolism conco rdant with TD. ABC1 is expressed on the plasma membrane and the Golgi compl ex, mediates apo-Al 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 invol ving vesicular budding between the Golgi and the plasma membrane are severe ly disturbed.