Combined hyperlipidemia in transgenic mice overexpressing human apolipoprotein CI

Abstract

We have generated transgenic mice over-expressing human apolipoprotein CI (apo CI) using the native gene joined to the downstream 154-bp liver- specific enhancer that we defined for apo E. Human apo CI (HuCI)-transgenic mice showed elevation of plasma triglycerides (mg/dl) compared to controls in both the fasted (211±81 vs 123±52, P = 0.0001) and fed (265±105 vs 146±68, P < 0.0001) states. Unlike the human apo CII (HuCII)- and apo CIII (HuCIII)transgenic mouse models of hypertriglyceridemia, plasma cholesterol was disproportionately elevated (95±23 vs 73±23, P = 0.002, fasted and 90±24 vs 61±14, P < 0.0001, fed). Lipoprotein fractionation showed increased VLDL and IDL+ LDL with an increased cholesterol/triglyceride ratio (0.114 vs 0.065, P = 0.02, in VLDL). The VLDL apo E/apo B ratio was decreased 3.4-fold (P = 0.05) and apo CII and apo CIII decreased in proportion to apo E. Triglyceride and apo B production rates were normal, but clearance rates of VLDL triglycerides and postlipolysis lipoprotein 'remnants' were significantly slowed. Plasma apo B was significantly elevated. Unlike HuCII- and HuCIII-transgenic mice, VLDL from HuCI transgenic mice bound heparin- Sepharose, a model for cell-surface glycosaminoglycans, normally. In summary, apo CI overexpression is associated with decreased particulate uptake of apo B-containing lipoproteins, leading to increased levels of several potentially atherogenic species, including cholesterol-enriched VLDL, IDL, and LDL.