Hepatic ATP-Binding Cassette Transporter A1 Is a Key Molecule in High-Density Lipoprotein Cholesteryl Ester Metabolism in Mice

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 26; no. 8; pp. 1821 - 1827
• Main Authors: Singaraja, Roshni R, Stahmer, Bjorn, Brundert, May, Merkel, Martin, Heeren, Joerg, Bissada, Nagat, Kang, Martin, Timmins, Jenelle M, Ramakrishnan, Rajasekhar, Parks, John S, Hayden, Michael R, Rinninger, Franz
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.08.2006; Hagerstown, MD Lippincott
• Subjects: Animals; Atherosclerosis (general aspects, experimental research); ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Biological and medical sciences; Blood and lymphatic vessels; Blood coagulation; Blood coagulation. Blood cells; Cardiology. Vascular system; Cholesterol - blood; Cholesterol Esters - metabolism; Chromosomes, Artificial, Bacterial - genetics; Chromosomes, Artificial, Bacterial - metabolism; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Fundamental and applied biological sciences. Psychology; Investigative techniques, diagnostic techniques (general aspects); Lipoproteins, HDL - metabolism; Lipoproteins, HDL - pharmacokinetics; Liver - metabolism; Medical sciences; Mice; Mice, Knockout - genetics; Mice, Transgenic - genetics; Molecular and cellular biology; Platelet; Scavenger Receptors, Class B - metabolism; Tissue Distribution; ABCA1; Digestive system; Liver; Rodentia; Cardiovascular disease; Metabolism; Uptake; Vascular disease; HDL; Vertebrata; Mammalia; Mouse; Animal; Atherosclerosis; selective uptake; Lipoprotein HDL; ATP; cholesteryl ester
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.0000229219.13757.a2

OBJECTIVE—Mutations in ATP-binding cassette transporter A1 (ABCA1), the cellular lipid transport molecule mutated in Tangier disease, result in the rapid turnover of high-density lipoprotein (HDL)–associated apolipoproteins that presumably are cleared by the kidneys. However, the role of ABCA1 in the liver for HDL apolipoprotein and cholesteryl ester (CE) catabolism in vivo is unknown. METHODS AND RESULTS—Murine HDL was radiolabeled with I in its apolipoprotein and with [H]cholesteryl oleyl ether in its CE moiety. HDL protein and lipid metabolism in plasma and HDL uptake by tissues were investigated in ABCA1-overexpressing bacterial artificial chromosome (BAC)–transgenic (BAC) mice and in mice harboring deletions of total (ABCA1) and liver-specific ABCA1 (ABCA1). In BAC mice with elevated ABCA1 expression, fractional catabolic rates (FCRs) of both the protein and the lipid tracer were significantly decreased in plasma and in the liver, yielding a diminished hepatic selective CE uptake from HDL. In contrast, ABCA1 or ABCA1 mice had significantly increased plasma and liver FCRs for both HDL tracers. An ABCA1 deficiency was associated with increased selective HDL CE uptake by the liver under all experimental conditions. CONCLUSIONS—Hepatic ABCA1 has a critical role for HDL catabolism in plasma and for HDL selective CE uptake by the liver.