transfer of free cholesterol ( 3 ). Moreover, PLTP has been implicated in hepatic apoB-containing particle secretion ( 4 ). Consistent with its role in lipoprotein metabolism, Pltp is regulated by liver X receptor (LXR) ( 5 ) and farnesoid X receptor (FXR) ( 6 ), which are regulators of bile metabolism. Pltp overexpression has been associated with increased cholesterol and phospholipids output via the bile ( 7 ).PLTP defi ciency in mice results in a large decrease in plasma lipid levels, including total cholesterol, cholesteryl ester, and phospholipids, when the mice are fed a chow diet ( 2, 8 ) or Western-type diet consisting of 20% milk fat plus 0.15% cholesterol ( 8 ). However, when fed a high-fat diet consisting of 20% saturated fat from coconut oil and 0.15% cholesterol (COD), Pltp knockout (KO) mice accumulate more free cholesterol and phospholipids than wildtype (WT) controls ( 8 ). On chow diet, Pltp KO/ Apoe KO mice have signifi cantly less atherosclerosis than Apoe KO controls ( 4 ).The role of plasma total cholesterol in atherogenesis has been well established. However, plasma cholesterol exists in two forms: cholesteryl ester and free (unesterifi ed) cholesterol. There is evidence suggesting that free cholesterol plays an important role in atherosclerosis. Free cholesterol has been observed in human atherosclerotic lesions, both intracellularly and extracellularly ( 9 ). Furthermore, free cholesterol accumulates more in severe lesions than in mild ones in the same aorta ( 10 ). In a cell culture model, free Abstract A high saturated fat diet induces free cholesterol and phospholipid accumulation in the plasma of phospholipid transfer protein ( Pltp )-defi cient mice. In this study, we examined the atherogenic consequence of this phenomenon and investigated the possible mechanism(s). Pltp KO/ Apoe KO mice that were fed a coconut oil-enriched high-fat diet (COD) for 7 weeks had higher plasma free cholesterol (149%), phospholipids (15%), and sphingomyelin (54%) than Apoe KO controls. In contrast to chow-fed animals, COD-fed Pltp KO/ Apoe KO mice had the same atherosclerotic lesion size as that of Apoe KO mice. Similar to Pltp KO mice, plasma from COD-fed Pltp KO /Apoe KO mice contained VLDL/ LDL-sized lamellar particles. Bile measurement indicated that COD-fed Pltp KO mice have 33% less hepatic cholesterol output than controls. In conclusion, COD-fed, Pltpdefi cient mice are no longer protected from atherosclerosis and have impaired biliary lipid secretion, which is associated with free cholesterol and phospholipid accumulation. -Yeang, C., S. Qin, K. Chen, D. Q-H. Wang, and X-C. Jiang. Diet-induced lipid accumulation in phospholipid transfer protein-defi cient mice: its atherogenicity and potential mechanism. J. Lipid Res. 2010. 51: 2993-3002.