The amino-terminal 1-185 domain of ApoE promotes the clearance of lipoprotein remnants in vivo. The carboxy-terminal domain is required for inductionof hyperlipidemia in normal and ApoE-deficient mice

Apolipoprotein E (apoE) promotes receptor-mediated catabolism of apoE-conta ining lipoprotein remnants. Impairments in remnant clearance are associated with type III hyperlipoproteinemia and premature atherosclerosis. In human s, apoE plasma levels correlate with plasma triglyceride levels, suggesting that excess apoE may also affect plasma triglyceride levels. We have used adenovirus-mediated gene transfer in mice to map the domains of apoE requir ed for cholesterol and triglyceride clearance, in vivo. Adenovirus expressi ng apoE3 and apoE4 at doses of (1-2) x 10(9) pfu increased plasma cholester ol and triglyceride levels in normal C57BL6 mice and failed to normalize th e high cholesterol levels of apoE-deficient mice due to induction of hypert riglyceridemia. In contrast, an adenovirus expressing the truncated apoE 1- 185 form normalized the cholesterol levels of E-/- mice and did not cause h ypertriglyceridemia. Northern blot analysis of hepatic RNA from mice expres sing the full-length and the truncated apoE forms showed comparable steady- state apoE mRNA levels of the full-length apoE forms that cause hyperlipide mia and the truncated apoE forms that do not cause hyperlipidemia. The find ings suggest that the amino-terminal residues 1-185 of apoE are sufficient for the clearance of apoE-containing lipoprotein remnants by the liver, whe reas domains of the carboxy-terminal one-third of apoE are required for apo E-induced hyperlipidemia.