Apolipoprotein E2 (Lys146→Gln) Causes Hypertriglyceridemia due to an Apolipoprotein E Variant–Specific Inhibition of Lipolysis of Very Low Density Lipoproteins–Triglycerides

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 20; no. 7; pp. 1800 - 1806
• Main Authors: de Beer, Femke, van Dijk, Ko Willems, Jong, Miek C, van Vark, Leonie C, van der Zee, Andre, Hofker, Marten H, Fallaux, Frits J, Hoeben, Rob C, Smelt, Augustinus H. M, Havekes, Louis M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.07.2000; Hagerstown, MD Lippincott
• Subjects: Adenoviridae - genetics; Alleles; Animals; Apolipoprotein E2; Apolipoprotein E3; Apolipoproteins E - blood; Apolipoproteins E - genetics; Biological and medical sciences; Disorders of blood lipids. Hyperlipoproteinemia; Gene Expression - physiology; Gene Transfer Techniques; Humans; Hydrolysis; Hyperlipoproteinemia Type III - genetics; Hyperlipoproteinemia Type III - metabolism; Hypertriglyceridemia - genetics; Hypertriglyceridemia - metabolism; Lipolysis - genetics; Lipoproteins, VLDL - metabolism; Liver - metabolism; Male; Medical sciences; Metabolic diseases; Mice; Mice, Knockout; Point Mutation; RNA, Messenger - analysis; Triglycerides - metabolism; Lipoprotein VLDL; Pathogenesis; Deficiency; Genetic variant; Rodentia; Metabolic diseases; Lipids; Hyperlipoproteinemia; Metabolism; Enzymopathy; Vertebrata; Mammalia; Transfection; Gene; Mouse; Apolipoprotein E; Hypertriglyceridemia; Animal; Mutation; Dyslipemia; Comparative study
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.20.7.1800

The apolipoprotein E2 (Lys146→Gln) variant is associated with a dominant form of familial dysbetalipoproteinemia. Heterozygous carriers of this variant have elevated levels of plasma triglycerides, cholesterol, and apolipoprotein E (apoE). It was hypothesized that the high amounts of triglycerides in the very low density lipoprotein (VLDL) fraction are due to a disturbed lipolysis of VLDL. To test this hypothesis, apoE knockout mice were injected with an adenovirus containing the human APOE*2 (Lys146→Gln) gene, Ad-E2(146), under the control of the cytomegalovirus promoter. ApoE knockout mice injected with an adenovirus vector encoding human apoE3 (Ad-E3) were used as controls. Five days after adenovirus injection, plasma cholesterol levels of mice injected with a high dose of Ad-E2(146) (2×10 plaque-forming units) were not changed compared with preinjection levels, whereas in the group who received a low dose of Ad-E2(146) (5×10 plaque-forming units) and in the groups injected with a low or a high dose of Ad-E3, plasma cholesterol levels were decreased 5-, 6-, and 12-fold, respectively. Plasma triglycerides were not affected in mice injected with Ad-E3. In contrast, a 7-fold increase in plasma triglycerides was observed in mice injected with the low dose of Ad-E2(146) compared with mice injected with Ad-E3. Injection with the high dose of Ad-E2(146) resulted in a dramatic increase of plasma triglycerides (50-fold compared with Ad-E3 injection). In vitro lipolysis experiments showed that the lipolysis rate of VLDLs containing normal amounts of apoE2 (Lys146→Gln) was decreased by 54% compared with that of VLDLs containing comparable amounts of apoE3. The in vivo VLDL-triglyceride production rate of Ad-E2(146)–injected mice was not significantly different from that of Ad-E3–injected mice. These results demonstrate that expression of apoE2 (Lys146→Gln) causes hypertriglyceridemia due to an apoE variant–specific inhibition of the hydrolysis of VLDL-triglycerides.