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

Background & Aims: Members of the family of ABC transporters are involved in different processes of sterol metabolism, and ABCA1 was recently identified as a key regulator of high-density lipoprotein (HDL) metabolism. Our aim was to further analyze the role of ABCA1 in cholesterol metabolism. Methods: ABCA1-deficient mice (ABCA1(-/-)) and wild-type mice were compared for different aspects of sterol metabolism, Intestinal cholesterol absorption was determined by a dual stable isotope technique, and analysis of fecal, plasma, and tissue sterols was performed by gas chromatography/ mass spectrometry. Key regulators of sterol metabolism were investigated by Northern and Western blot analyses or enzyme activity assays, Results: ABCA1-disrupted sv129/C57BL/6 hybrid mice showed a significant reduction in intestinal cholesterol absorption. The decrease in cholesterol absorption was followed by an enhanced fecal loss of neutral sterols, whereas fecal bile acid excretion was not affected. Total body cholesterol synthesis was significantly increased, with enhanced 3-hydroxy-3-methyglutaryl- coenzyme A (HMG-CoA) reductase observed in adrenals and spleen, In addition, ABCA1(-/-) mice showed markedly increased concentrations of cholesterol precursors in the plasma, lung, 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 affected by a lack of ABCA1 function.