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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:668.)
© 2003 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Amino Terminal 38.9% of Apolipoprotein B-100 Is Sufficient to Support Cholesterol-Rich Lipoprotein Production and Atherosclerosis

Zhouji Chen; Robin L. Fitzgerald; Jeffrey E. Saffitz; Clay F. Semenkovich; Gustav Schonfeld

From the Department of Medicine, Division of Atherosclerosis, Nutrition and Lipid Research (Z.C., R.L.F., C.F.S., G.S), and the Department of Pathology (J.E.S.), Washington University School of Medicine, St. Louis, Mo.

Correspondence to Zhouji Chen, PhD, Department of Medicine, Division of Atherosclerosis, Nutrition and Lipid Research, Washington University School of Medicine, Box 8046, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail zchen{at}im.wustl.edu

Objective— Carboxyl terminal truncation of apolipoprotein (apo)B-100 and apoB-48 impairs their capacity for triglyceride transport, but the ability of the resultant truncated apoB to transport cholesterol and to support atherosclerosis has not been adequately studied. The atherogenicity of apoB-38.9 was determined in this study by using our apoB-38.9–only (Apob^38.9/38.9) mice.

Methods and Results— ApoB-38.9-lipoproteins (Lp-B38.9) circulate at very low levels in Apob^38.9/38.9 mice as small LDLs or HDLs. Disruption of apoE gene in these mice caused accumulation of large amounts of ßVLDL-like LpB-38.9 in plasma. These ßVLDL particles were more enriched with cholesteryl esters but poor in triglycerides compared with the apoB-48-ßVLDL of the apoB-wild-type/apoE-null (Apob^+/+/Apoe^-/-) mice. Likewise, apoB-38.9-VLDL secreted by cultured Apob^38.9/38.9 mouse hepatocytes also had higher ratios of total cholesterol to triglycerides than apoB-48-VLDL secreted by the apoB-48–only hepatocytes. Thus, despite its impaired triglyceride-transporting capacity, apoB-38.9 has a relatively intact capacity for cholesterol transport. Spontaneous aortic atherosclerotic lesions were examined in apoB-38.9–only/apoE-null (Apob^38.9/38.9/Apoe^-/-) mice at ages 9 and 13 months. Extensive lesions were found in the Apob^38.9/38.9/Apoe^-/- mice as well as in their Apob^+/38.9/Apoe^-/- and Apob^+/+/Apoe^-/- littermates.

Conclusion— Deleting the C-terminal 20% from apoB-48 does not impair its ability to transport cholesterol and to support atherosclerosis, thus narrowing the "atherogenic region" of apoB.

Key Words: atherosclerosis • apolipoprotein B • animal model • VLDL secretion • cholesterol secretion • liver