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Remnant lipoproteins, apolipoprotein E4 and atherosclerosis

Institution: J. David Gladstone Institutes
Investigator(s): Robert Raffai, Ph.D.
Award Cycle: 2001 (Cycle 10) Grant #: 10KT-0318 Award: $400,500
Subject Area: Cardiovascular Disease
Award Type: New Investigator Awards
Abstracts

Initial Award Abstract
Heart disease and stroke can result from high levels of fat (lipids) in the blood that cause atherosclerosis or fatty deposits in arteries (“clogged arteries”) that block normal blood flow. Two classes of blood lipids that contribute to atherosclerosis are low density lipoproteins (LDL) and remnant lipoproteins. Cigarette smoking contributes to atherosclerosis by raising the levels of remnant lipoproteins and by oxidizing plasma lipoproteins. Oxidized remnant lipoproteins and oxidized LDL are both potent contributors to atherosclerosis.

Apolipoprotein (apo) E is a critical mediator of plasma lipoprotein metabolism in the blood. One of the three common forms of this protein, apoE4, is associated with increased LDL levels and premature atherosclerosis, further increasing the risk of tobacco-related disease. How apoE4 raises LDL levels is not fully understood.

To address this issue, I created mice that express a mouse equivalent of human apoE4 (“apoE4 mice”), and not normal mouse apoE. However, through genetic manipulation, these mice have very low levels of “mouse apoE4” expression throughout the body. These low plasma apoE levels are sufficient to maintain normal remnant lipoprotein metabolism in mice fed a chow diet but not in those fed a high-fat diet. This effect can be fully reversed to restore normal levels of mouse apoE4, either in all or in selected tissues.

I propose to use apoE4 mice with low or normal levels of apoE to investigate some key unanswered questions regarding remnant lipoprotein clearance and atherosclerosis. First, I will determine the minimal amount of plasma apoE required for normal remnant lipoprotein clearance and determine the relative importance of apoE produced in the liver or elsewhere in the body in this process. To lower further the expression of apoE in mice expressing low levels of apoE, I will mate apoE4 mice with mice which do not have apoE. These mice will have half the level of apoE seen in the parents. These mice will be fed a chow diet, and remnant clearance will be assessed.

Second, I will determine if apoE can reverse the clogged arteries caused by a high-fat diet. After mice with low levels of apoE are fed a high-fat diet for 3 months, normal apoE expression will be restored, and its effects on reversing the clogged arteries will be assessed.

Third, I will determine the amount of plasma apoE that is derived from macrophages, a type of blood cell found in atherosclerotic lesions. ApoE produced by macrophages may protect against the development of atherosclerosis. I will test this hypothesis by restoring normal apoE expression in macrophages only. These mice will allow me to determine whether low levels of apoE produced by macrophages are sufficient to prevent atherosclerosis. Finally, I will elucidate the mechanism that results in the high LDL levels associated with apoE4.

A better understanding of how apoE lowers plasma remnant lipoprotein levels and modulates atherosclerosis holds the potential to define novel treatments to lower plasma lipids and reverse existing atherosclerotic deposits. Lowering plasma lipid levels is critical to counteract the deleterious effects of smoking that contribute to atherosclerosis and lead to heart disease and stroke.
Publications

Introduction of human apolipoprotein E4 domain interaction into mouse apolipoprotein E.
Periodical: Proceedings of the National Academy of Sciences of the United States of America Index Medicus:
Authors: Raffai RL, Dong L-M, Farese RV Jr., Weisgraber KH ART
Yr: 2001 Vol: 98 Nbr: Abs: Pg: 11587-11591

Hypomorphic apolipoprotein E mice: A new model of conditional gene repair to examine apolipoprotein E-mediated metabolism.
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Raffai RL, and Weisgraber KH ART
Yr: 2992 Vol: 277 Nbr: Abs: Pg: 11064-11068

Hepatocyte-derived apoE is more effective than non-hepatocyte-derived apoE in remnant lipoprotein clearance.
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Raffai RL, Hasty AH, Wang Y, Mettler SE, Sanan DA, Linton ML, Fazio S, Weisgraber KH ART
Yr: 2003 Vol: 278 Nbr: Abs: Pg: 11670-11675