Abstract
The molecular mechanisms of hypertriglyceridemia (HTG), a common lipid metabolic disorder in humans, often of genetic origin, are not well understood. In studying the effect of apolipoprotein (apo) E on the metabolism of triglyceride-rich lipoproteins, we found that expressing high plasma levels of human apoE3 in transgenic mice lacking endogenous mouse apoE caused HTG. These transgenic animals had 3-fold higher plasma triglyceride levels, higher very low density lipoproteins (VLDL), and lower high density lipoproteins than did nontransgenics. Removing one or both low density lipoprotein receptor alleles in the apoE3-overexpressing mice caused severe HTG (8-11-fold over nontransgenics) and increased VLDL and decreased low and high density lipoproteins, and apoE3-enriched VLDL were markedly depleted in apoC-II. At least two mechanisms could explain HTG associated with apoE3 overexpression: stimulated VLDL triglyceride production and impaired VLDL lipolysis. The apoE3 mice with HTG had a 50% increase in hepatic VLDL triglyceride production. Furthermore, overexpression of apoE (E2, E3, or E4) in cultured hepatocytes (McA-RH7777 cells) correlated positively with secretion of VLDL into the medium. However, apoE3 overexpression-associated HTG was only partially explained by VLDL overproduction, as lipoprotein lipase-mediated VLDL lipolysis was also decreased 20-86% depending on apoE3 levels, most likely by displacing or masking apoC-II on the particles. In human subjects, HTG correlated positively with increased VLDL triglyceride and plasma and VLDL apoE levels. However, plasma and VLDL apoE correlated negatively with VLDL apoC-II levels and lipoprotein lipase-mediated VLDL lipolysis. Thus, optimal expression of apoE is crucial for normal metabolism of triglyceride-rich lipoproteins, and overexpression and/or accumulation of apoE may contribute to HTG by stimulating VLDL triglyceride production and by impairing VLDL lipolysis. The apoE3-overexpressing mice will be useful for studying the pathophysiology of this disorder.
Highlights
The molecular mechanisms of hypertriglyceridemia (HTG), a common lipid metabolic disorder in humans, often of genetic origin, are not well understood
ApoE3 overexpression– associated HTG was only partially explained by very low density lipoproteins (VLDL) overproduction, as lipoprotein lipase–mediated VLDL lipolysis was decreased 20 – 86% depending on apoE3 levels, most likely by displacing or masking apoC-II on the particles
Optimal expression of apoE is crucial for normal metabolism of triglyceriderich lipoproteins, and overexpression and/or accumulation of apoE may contribute to HTG by stimulating VLDL triglyceride production and by impairing VLDL lipolysis
Summary
Materials—A Superose 6 column purchased from Amersham Pharmacia Biotech was used on a Pharmacia fast protein liquid chromatography system. Cholesterol and triglyceride standards were from Abbott (North Chicago, IL) and Boehringer Mannheim (Mannheim, Germany), respectively. The automated system for lipid analysis (Kinetic Microplate Reader) was from Molecular Devices (Menlo Park, CA). [14C]Acetate, and ECL chemiluminescence detection kits for Western blots were purchased from Amersham Life Science (Little Chalfont, Buckinghamshire, United Kingdom). Transgenic Mice—Hemizygous human apoE3 transgenic mice (ICR strain) were produced at the Gladstone Institute of Cardiovascular Disease with a DNA construct containing human apoE3 genomic DNA. 0 23 Ϯ 3 54 Ϯ 4 a p Ͻ 0.01 versus nontransgenic mice. B p Ͻ 0.05 versus hE3low/mE0 mice. 0 23 Ϯ 3 54 Ϯ 4 a p Ͻ 0.01 versus nontransgenic mice. b p Ͻ 0.05 versus hE3low/mE0 mice. c p Ͻ 0.01 versus LDLR1 mice. d p Ͻ 0.01 versus LDLR0 mice
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