Overexpression of Apolipoprotein E in Transgenic Mice: Marked Reduction in Plasma Lipoproteins Except High Density Lipoprotein and Resistance Against Diet-Induced Hypercholesterolemia

Apolipoprotein E (apoE) has a high affinity to cell-surface low density lipoprotein (LDL) receptor. To determine the role of apoE in plasma lipoprotein metabolism, transgenic mouse lines with integrated rat apoE gene under the control of the metallothionein promoter were established. We found that a...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 89; no. 5; pp. 1750 - 1754
Main Authors:	Shimano, Hitoshi, Yamada, Nobuhiro, Katsuki, Motoya, Shimada, Masaka, Gotoda, Takanari, Harada, Kenji, Murase, Toshio, Fukazawa, Chikafusa, Takaku, Fumimaro, Yazaki, Yoshio
Format:	Journal Article
Language:	English
Published:	Washington, DC National Academy of Sciences of the United States of America 01-03-1992 National Acad Sciences National Academy of Sciences
Subjects:	Analytical, structural and metabolic biochemistry Animals Apolipoproteins E - physiology Biological and medical sciences Cholesterol Cholesterol - blood Cholesterols Diet Fundamental and applied biological sciences. Psychology Gene Expression Genes HDL lipoproteins Heterozygotes Homozygotes Hypercholesterolemia - prevention & control Lipoproteins Lipoproteins - blood Lipoproteins, HDL - blood Lipoproteins, myelin Liver Medical research Mice Mice, Transgenic Proteins Rats RNA, Messenger - genetics Transgenic animals Triglycerides Triglycerides - blood Zinc Plasma Rodentia Transgenic animal Gene overexpression Supplemented diet Lipoprotein Metabolism Triglyceride Cholesterol Resistance Vertebrata Regulation(control) Mammalia Hypercholesterolemia Mouse
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Summary:	Apolipoprotein E (apoE) has a high affinity to cell-surface low density lipoprotein (LDL) receptor. To determine the role of apoE in plasma lipoprotein metabolism, transgenic mouse lines with integrated rat apoE gene under the control of the metallothionein promoter were established. We found that a high expressor line produced rat apoE mainly in the liver, and the gene product was almost entirely associated with plasma lipoproteins. The plasma level of rat apoE in homozygotes for the transgene was 17.4 mg/dl after zinc induction (vs. 4.56 mg/dl of mouse apoE in controls). In this group, plasma cholesterol and triglyceride levels were 43% and 68% reduced as compared with controls, respectively. Heterozygotes showed decreases in both lipids to a lesser extent. Gel filtration chromatography showed that lipid reduction was mainly due to decreased very low density lipoproteins (VLDL) and LDL. Especially in zinc-treated homozygotes, VLDL had almost disappeared, and a remarkable decrease in LDL and a slight decrease in high density lipoprotein were also observed. Consistently, the plasma level of apoB, a structural protein of VLDL and LDL, was 78% lower than that of controls, indicating a marked reduction in lipoproteins containing apoB. Furthermore, the transgenic mice, in contrast to controls, did not develop hypercholesterolemia when fed a high cholesterol diet. These results demonstrated that overexpression of apoE reduces plasma cholesterol and triglyceride levels and prevents diet-induced hypercholesterolemia. From dramatic and dose-related decreases in plasma lipoproteins in transgenic mice, we conclude that apoE plays a key role in plasma lipoprotein metabolism.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.89.5.1750