ATP-binding cassette transporter A1 (ABCA1) affects total body sterol metabolism

Background & Aims: Members of the family of ABC transporters are involved i n different processes of sterol metabolism, and ABCA1 was recently identifi ed as a key regulator of high-density lipoprotein (HDL) metabolism. Our aim was to further analyze the role of ABCA1 in cholesterol metabolism. Method s: ABCA1-deficient mice (ABCA1(-/-)) and wild-type mice were compared for d ifferent aspects of sterol metabolism, Intestinal cholesterol absorption wa s determined by a dual stable isotope technique, and analysis of fecal, pla sma, and tissue sterols was performed by gas chromatography/ mass spectrome try. Key regulators of sterol metabolism were investigated by Northern and Western blot analyses or enzyme activity assays, Results: ABCA1-disrupted s v129/C57BL/6 hybrid mice showed a significant reduction in intestinal chole sterol absorption. The decrease in cholesterol absorption was followed by a n enhanced fecal loss of neutral sterols, whereas fecal bile acid excretion was not affected. Total body cholesterol synthesis was significantly incre ased, with enhanced 3-hydroxy-3-methyglutaryl- coenzyme A (HMG-CoA) reducta se observed in adrenals and spleen, In addition, ABCA1(-/-) mice showed mar kedly increased concentrations of cholesterol precursors in the plasma, lun g, intestine, and feces, Reduced HMG-CoA reductase messenger RNA and enzyme activity in the liver suggest that enhanced cholesterol synthesis in ABCA1 (-/-) mice occurs in peripheral tissues rather than the liver. Conclusions: The metabolism of cholesterol and cholesterol precursors is markedly affec ted by a lack of ABCA1 function.