The incidence of premature coronary atherosclerosis in the human population is highly correlated to decreased concentrations of plasma high density lipoproteins (HDL) and its major apoprotein, apolipoprotein A-I (apo A-I). Transgenic and knockout mouse studies have shown that circulating HDL apo A-I primarily plays a """"""""protective function"""""""" in response to high levels of atherogenic lipoproteins through its ability to accept, organize and transport cholesterol out of the artery to the liver for uptake and excretion into bile. This """"""""reverse cholesterol transport pathway"""""""" is highly dependent upon apo A-I's ester conversion in the plasma. Blockage or reduction in apo A-I's ability to carry out this function can lead to reduced reverse cholesterol transport and inefficient removal of peripheral tissue cholesterol. Data from the applicants' laboratory show that structural alterations in the conformation of plasma apo A-I can have a more profound effect on HDL apo A-I formation and maturation than merely the absence of native apo A-I alone. Their studies show that LCAT activation and thus, plasma cholesterol esterification is inhibited by the presence of a mutant form of apo A-I in plasma. The mutant apo A-I does this by inhibiting plasma cholesterol esterification even in plasma containing native or wild type apo A-I. Thus, they propose to investigate the molecular and cellular basis for the severe disruption in HDL metabolism resulting from the hepatic expression of the mutant human apo A-I, termed 6 apo A-I. This mutant of apo A-I lacks repeat 6, a single proline punctuated 22-mer and has been shown to have a similar plasma lipoprotein phenotype to a known human apo A-I mutation, called apo A-I. In a newly created transgenic mouse model, designated Tg6 apo A-I the applicants propose to conduct dietary-cholesterol feeding studies to determine if mutant apo A-I protects against atherosclerosis in mice with hypercholesterolemia. They also plan to elucidate the molecular and cellular basis for 6 apo A-I's disruption of HDL apo A-I metabolism.
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