Expression of human lecithin cholesterol acyltransferase (LCAT) in mice (LCAT-Tg) leads to increased high density lipoprotein (HDL) cholesterol levels but paradoxically, enhanced atherosclerosis. We have hypothesized that the absence of cholesteryl ester transfer protein (CETP) in LCAT-Tg mice facilitates the accumulation of dysfunctional HDL leading to impaired reverse cholesterol transport and the development of a pro-atherogenic state. To test this hypothesis we crossbred LCAT-Tg with CETP-Tg mice. On both regular chow and high fat, high cholesterol diets, expression of CETP in LCAT-Tg mice reduced total cholesterol (؊39% and ؊13%, respectively; p < 0.05), reflecting a decrease in HDL cholesterol levels. CETP normalized both the plasma clearance of Increased plasma levels of high density lipoproteins (HDL) 1 are powerful indicators of low cardiovascular risk in humans (1-3). This relationship may in part be indirect, reflecting the fact that high levels of HDL are a marker for efficient clearance of pro-atherogenic remnant particles from the circulation (4). However, increased plasma HDL levels achieved by either infusion of HDL or overexpression of the apoA-I gene (5-8) protect against the development of atherosclerosis in different animal models, indicating a direct anti-atherogenic role of HDL. The mechanism underlying this relationship is poorly understood. Potential anti-atherogenic properties of HDL include antioxidant effects (9, 10) as well as the ability to prevent monocyte recruitment into the intima (11, 12), to inhibit the aggregation of atherogenic lipoproteins (13, 14), and to serve as a thrombolytic agent (15). HDL has also been proposed to play a major role in reverse cholesterol transport, a process that involves the movement of cholesterol from peripheral cells to the liver for removal from the body (16 -19). Thus, raising plasma HDL by dietary, pharmacologic, or genetic interventions may be an effective strategy for the prevention of cardiovascular disease in humans.Cholesteryl ester transfer protein (CETP) and lecithin cholesterol acyltransferase (LCAT) are two key proteins that modulate the plasma concentrations of HDL. LCAT mediates the esterification of free cholesterol on plasma lipoproteins, thereby converting discoidal, nascent HDL particles into mature spherical HDL containing a central core of cholesteryl esters (CE) (16,19). Overexpression of LCAT in transgenic rabbits (20, 21) increases the plasma HDL cholesterol levels and significantly reduces aortic atherosclerosis. LCAT transgenic mice (LCAT-Tg) also have elevated HDL cholesterol levels (22-24). However, high plasma HDL concentrations are associated with either no change (25) or enhanced diet-induced atherosclerosis in LCAT-Tg mice (26).CETP is another key protein that modulates the plasma levels of HDL. CETP promotes the transfer of CE from HDL to apoB-containing lipoproteins in exchange for triglyceride (19,(27)(28)(29). The absence of atherosclerosis in some of the first CETP-deficient Japanese patients to be described (30...

In earlier studies we identified a putative repressor of the human ␤-globin gene, termed beta protein 1 (BP1), which binds to two silencer DNA sequences upstream of the adult human ␤-globin gene and to a negative

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