Treatment of severe hypercholesterolemia in apolipoprotein E-deficient mice by bone marrow transplantation.
Apo E, a key regulator of cholesterol-rich lipoprotein metabolism, is synthesized by numerous extrahepatic tissues. Although its synthesis in macrophages is documented, the contribution of macrophage-derived apo E to hepatic clearance of serum cholesterol is unknown. To address this issue bone marrow transplantation was performed on hypercholesterolemic apo E-deficient mice with either syngeneic apo E-deficient mouse bone marrow cells (E0-control) or wild-type mouse bone marrow cells expressing apo E (E0-treated). E0-control and E0-treated mice were fed either a regular chow diet or an atherogenic diet (designated E0-control-HF and E0-treated-HF). Serum cholesterol levels dropped dramatically in the E0-treated mice largely due to a reduction in their VLDL cholesterol. No changes were seen in the E0-control mice. After 4 wk serum cholesterol in E0-treated-HF mice was about four-fold lower compared to E0-control-HF animals. Moreover, the extent of atherosclerosis in the E0-treated-HF mice after 14-16 wk was greatly reduced. Wild-type apo E mRNA was detected in the liver, spleen, and brain of the E0-treated mice indicating that apo E gene transfer was successfully achieved through bone marrow transplantation. More importantly, the level of apo E expression was sufficient to reduce the severe hypercholesterolemia of the apo E-deficient mice fed either chow or atherogenic diets.
Boisvert
W A
WA
Department of Immunology, Scripps Research Institute, La Jolla, California 92037, USA.
Spangenberg
J
J
Curtiss
L K
LK
D000483:Alleles; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D001161:Arteriosclerosis / Q000209:etiology / Q000517:prevention & control*; D001483:Base Sequence; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000097:blood; D004036:Diet, Atherogenic; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006938:Hyperlipoproteinemia Type II / Q000150:complications / Q000628:therapy*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009928:Organ Specificity; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis
D001057:Apolipoproteins E; D012333:RNA, Messenger; D002784:Cholesterol