Apolipoprotein E4 exaggerates diabetic dyslipidemia and atherosclerosis in mice lacking the LDL receptor

OBJECTIVE—We investigated the differential roles of apolipo-protein E (apoE) isoforms in modulating diabetic dyslipidemia— a potential cause of the increased cardiovascular disease risk of patients with diabetes. RESEARCH DESIGN ANDMETHODS—Diabetes was induced using streptozotocin (STZ) in human apoE3 (E3) or human apoE4 (E4) mice deficient in the LDL receptor (LDLR2/2). RESULTS—Diabetic E3LDLR2/2 and E4LDLR2/2 mice have in-distinguishable levels of plasma glucose and insulin. Despite this, diabetes increased VLDL triglycerides and LDL cholesterol in E4LDLR2/2 mice twice as much as in E3LDLR2/2 mice. Diabetic E4LDLR2/2 mice had similar lipoprotein fractional catabolic rates compared with diabetic E3LDLR2/2 mice but had larger hepatic fat stores and increased VLDL secretion. Diabetic E4LDLR2/2 mice demonstrated a decreased reliance on lipid a