Combined Hyperlipidemia in Transgenic Mice Overexpressing Human Apolipoprotein Cl

J Clin Invest. 1996 Aug 1;98(3):846-55. doi: 10.1172/JCI118857.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apolipoprotein C-I
  • Apolipoproteins B / metabolism
  • Apolipoproteins C / genetics*
  • Apolipoproteins C / physiology
  • Cholesterol / blood
  • Female
  • Humans
  • Hyperlipidemias / etiology*
  • Lipoproteins / blood
  • Lipoproteins, VLDL / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Transgenic

Substances

  • Apolipoprotein C-I
  • Apolipoproteins B
  • Apolipoproteins C
  • Lipoproteins
  • Lipoproteins, VLDL
  • Cholesterol