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 (EO-control) or wildtype mouse bone marrow cells expressing apo E (EO-treated), EO-control and EO-treated mice were fed either a regular chow diet or an atherogenic diet (designated EO-control-HF and EO-treated-HF). Serum cholesterol levels dropped dramatically in the EO-treated mice largely due to a reduction in their VLDL cholesterol, No changes were seen in the EO-control mice, After 4 wk serum cholesterol in EO-treated-HF mice was about four-fold lower compared to EO-control-HF animals, Moreover, the extent of atherosclerosis in the EO-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 EO-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.