Combined hyperlipidemia in transgenic mice overexpressing human apolipoprotein Cl.
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.
Shachter
N S
NS
Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA. nss5@columbia.edu
Ebara
T
T
Ramakrishnan
R
R
Steiner
G
G
Breslow
J L
JL
Ginsberg
H N
HN
Smith
J D
JD
D000818:Animals; D053302:Apolipoprotein C-I; D001055:Apolipoproteins B / Q000378:metabolism; D001056:Apolipoproteins C / Q000235:genetics* / Q000502:physiology; D002784:Cholesterol / Q000097:blood; D005260:Female; D006801:Humans; D006949:Hyperlipidemias / Q000209:etiology*; D008074:Lipoproteins / Q000097:blood; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic
D053302:Apolipoprotein C-I; D001055:Apolipoproteins B; D001056:Apolipoproteins C; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D002784:Cholesterol