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Abstract-The plasma cholesteryl ester transfer protein (CETP) plays a major role in the catabolism of HDL cholesteryl ester (CE). CETP transgenic mice have decreased HDL cholesterol levels and have been reported to have either increased or decreased early atherosclerotic lesions. To evaluate the impact of CETP expression on more advanced forms of atherosclerosis, we have cross-bred the human CETP transgene into the apoE knock-out (apoE0) background with and without concomitant expression of the human apo A-I transgene. In this model the CETP transgene is induced to produce plasma CETP levels 5 to 10 times normal human levels. CETP expression resulted in moderately reduced HDL cholesterol (34%) in apoE0 mice and markedly reduced HDL cholesterol (76%) in apoE0/apoA1 transgenic mice. After injection of radiolabeled HDL CE, the CETP transgene significantly delayed the clearance of CE radioactivity from plasma in apoE0 mice, but accelerated the clearance in apoE0/apoA1 transgenic mice. ApoE0/CETP mice displayed an increase in mean atherosclerotic lesion area on the chow diet (approximately 2-fold after 2 to 4 months, and 1.4-to 1.6-fold after 7 months) compared with apoE0 mice (PϽ0.02). At 7 months apoA1 transgene expression resulted in a 3-fold reduction in mean lesion area in apoE0 mice (PϽ0.001). In the apoE0/apoA1 background, CETP produced an insignificant 1.3-to 1.7-fold increase in lesion area. In further studies the CETP transgene was bred onto the LDL receptor knock-out background (LDLR0). After 3 months on the Western diet, the mean lesion area was increased 1.8-fold (PϽ0.01) in LDLR0/CETP mice, compared with LDLR0 mice. These studies indicate that CETP expression leads to a moderate increase in atherosclerosis in apoE0 and LDLR0 mice, and suggest a proatherogenic effect of CETP activity in metabolic settings in which clearance of remnants or LDL is severely impaired. However, apoA1 overexpression has more dramatic protective effects on atherosclerosis in apoE0 mice, which are not significantly reversed by concomitant expression of CETP. Key Words: atherogenesis Ⅲ transgenic mice Ⅲ fractional catabolic rate Ⅲ HDL metabolism T he plasma cholesteryl ester transfer protein (CETP) mediates the transfer of HDL cholesteryl ester (CE) to triglyceride-rich lipoproteins and thereby increases the catabolism of HDL CEs. 1 The role that CETP plays in atherosclerosis appears to depend on the accompanying lipoprotein pattern and genetic background. In humans and in murine models of atherosclerosis, CETP can be either antiatherogenic or proatherogenic.In human genetic deficiency of CETP, HDL levels are markedly elevated in homozygotes and moderately elevated in heterozygotes. 2,3 The dramatic effects of human genetic CETP deficiency on HDL levels suggested the possibility that CETP inhibition by drugs or other interventions might be a therapeutic strategy to increase HDL levels and possibly to inhibit the progression of atherosclerosis. 4 For subjects with CETP deficiency and HDL cholesterol Ͼ60 mg/dL, there is a low preva...

Familial combined hyperlipidemia (FCHL) is a common inherited lipid disorder, affecting 1 to 2 percent of the population in Westernized societies. Individuals with FCHL have large quantities of very low density lipoprotein (VLDL) and low density lipoprotein (LDL) and develop premature coronary heart disease. A mouse model displaying some of the features of FCHL was created by crossing mice carrying the human apolipoprotein C-III (APOC3) transgene with mice deficient in the LDL receptor. A synergistic interaction between the apolipoprotein C-III and the LDL receptor defects produced large quantities of VLDL and LDL and enhanced the development of atherosclerosis. This mouse model may provide clues to the origin of human FCHL.

IntroductionThe plasma cholesteryl ester transfer protein (CETP) mediates the exchange of HDL cholesteryl esters (CE) The metabolism of HDL is regulated, in part, by the activities of lipases and lipid transfer proteins (1). Cholesteryl esters, generated in HDL by lecithin:cholesterol acyltransferase, are exchanged with triglycerides of VLDL, as a result of the activity of cholesteryl ester transfer protein (CETP)'. The subsequent activity of hepatic lipase on triglyceride-enriched HDL results in a decrease in HDL size and catabolism of the major apoliprotein of HDL, apoA-I (2). In a striking demonstration of the interaction of hypertriglyceridemia with cholesteryl ester transfer processes, hypertriglyceridemic apoC-II transgenic mice show profound reductions in HDL cholesterol and apoA-I when crossed with human CETP/apoA-I transgenic mice, to produce apoA-I/CETP/apoC-llH transgenic mice (3). In addition to plasma triglyceride concentration, effective plasma CETP activity is also influenced by changes in CETP concentration, such as those resulting from changes in dietary cholesterol or probucol therapy (4, 5).HDL is thought to mediate the reverse transport of cholesterol from peripheral tissues to the liver (6). In addition to this well-known role, Ulevitch et al. (7) have suggested another, novel function for HDL, namely to bind bacterial lipopolysaccharide (endotoxin) and thereby to modulate its biological effects. The binding of endotoxin to HDL can prevent endotoxininduced death (8). Harris et al. (9) have shown that VLDL and chylomicrons can also bind endotoxin, and protect mice against endotoxin-induced death. However, the potency of HDL appeared to be greater than that of other lipoproteins (9), and the molar concentrations of HDL in plasma are usually higher than other lipoproteins. Another role of HDL may be to provide cholesterol for adrenal corticosteroid synthesis ( 10-12), a function that could be particularly important during stress (13).The purpose of the present study was to examine the possible regulation of CETP gene expression in response to LPS administration. We suspected that CETP might be altered by LPS, since LPS has profound effects on lipoprotein metabolism and is known to regulate lipoprotein lipase and LCAT activities ( 14,15

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