Kinetic characteristics and regulation of HDL cholesteryl ester and apolipoprotein transport in the apoA-I 2 / 2 mouse

The concentration dependence and tissue distribution of high density lipoprotein (HDL) cholesteryl ester and apolipoprotein (apo) transport were determined in apoA-I knockout mice (apoA-I 2 / 2 ) that lack normal HDL in plasma. Rates of HDL cholesteryl ester clearance were highly sensitive to plasma HDL cholesteryl ester concentrations with clearance rates falling by 80% in the liver and by 95% in the adrenal glands when plasma HDL cholesteryl ester concentrations were acutely raised to levels normally seen in control mice ( , 50 mg/dl). With the exception of the brain, saturable HDL cholesteryl ester uptake was demonstrated in all tissues of the body, with the adrenal glands and liver manifesting the highest maximal transport rates (J m ). The plasma concentration of HDL cholesteryl ester necessary to achieve half-maximal transport (K m ) equaled 4 mg/dl in the adrenal glands and liver; as a consequence, HDL cholesteryl ester uptake by these organs is maximal (saturated) at normal plasma HDL concentrations in the mouse. When expressed per whole organ, the liver was the most important site of HDL cholesteryl ester clearance accounting for , 72% of total HDL cholesteryl ester turnover at normal plasma HDL concentrations. HDL cholesteryl ester transporter activity and scavenger receptor type B1 (SR-BI) protein and mRNA levels were not up-regulated in any organ of apoA-I 2 / 2 mice even though these animals lack normal HDL. — Spady, D. K. , L. A. Woollett, R. S. Meidell, and H. H. Hobbs. Kinetic characteristics and regulation of HDL cholesteryl ester and apolipoprotein transport in the apoA-I 2 / 2 mouse. J. Lipid Res. 1998. 39: 1483– 1492. Supplementary key words HDL • cholesteryl ester transport • apoA-I • liver • lipoproteins • reverse cholesterol transport An inverse relationship exists between the plasma concentration of high density lipoprotein (HDL) cholesterol and the risk of clinical coronary heart disease (1–3). Although the mechanisms responsible for this relationship are poorly understood, the protective effect of HDL is usually attributed to its role in maintaining sterol balance in extrahepatic tissues. Cholesterol that is acquired by most extrahepatic tissues (from de novo synthesis or lipoprotein uptake) must be returned to the liver for excretion in a process that has been termed reverse (4, 5) or centripetal (6) cholesterol transport. Reverse cholesterol transport is initiated in extrahepatic tissues by the transfer of unesterified cholesterol from cell membranes to nascent HDL (4, 5). A portion of this cholesterol is esterified by lecithin:cholesterol acyltransferase and partitions into the hydrophobic core of the HDL particle. HDL cholesteryl esters are cleared from plasma via several pathways including 1 ) transfer to lower density lipoproteins with subsequent uptake via the LDL receptor pathway (7), 2 ) uptake of the whole HDL particle (8), and 3 ) selective uptake of HDL cholesteryl esters resulting in an HDL particle of reduced size and cholesteryl ester content (9, 10). This latter process is likely mediated by the scavenger receptor type B1 (SR-BI), which was shown to mediate selective cholesteryl ester uptake when transfected into cells