Free cholesterol deposition in the cornea of human apolipoprotein A-II transgenic mice with functional lecithin: cholesterol acyltransferase deficiency.
We have developed several lines of transgenic animals that overexpress different levels of human apolipoprotein A-II (apoA-II). The 11.1 transgenic line has human apoA-II in plasma at threefold the level in normolipidemic humans and a functional lecithin:cholesterol acyltransferase (LCAT) deficiency. The latter is a biochemical phenotype similar to that of fish-eye disease (FED), which is characterized by free cholesterol (FC) and phospholipid accumulation in the cornea, leading to opacity and impaired vision. To assess whether the metabolic alterations in these mice also lead to lipid accumulation in the cornea, we fed them on a long-term regular chow or high-fat/high-cholesterol (HF/HC) diet. The 11.1 transgenic mice showed a moderate accumulation of FC in the cornea, but only when fed the regular chow diet. This FC accumulation was less severe than the accumulation described in FED, which may explain the lack of corneal opacity in these mice. Electron microscopy and immunoblotting analysis of the cornea of 11.1 transgenic mice in comparison to control mice showed (1) a mild but nevertheless more intense intracytoplasmatic lipid particle deposition in the epithelial cells and (2) a decrease of immunoreactive apoA-I in the area of Bowman's layer and at the superficial stroma. The serum capacity to cause cholesterol efflux from rat fibroblasts was decreased in 11.1 transgenic mice, but only in those fed a regular chow diet. We conclude that 11.1 human apoA-II transgenic mice may be a useful model for studies of early lipid deposition in the cornea and its possible prevention.
Julve-Gil
J
J
Servei de Bioquímica and Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Ruiz-Pérez
E
E
Casaroli-Marano
R P
RP
Marzal-Casacuberta
A
A
Escolà-Gil
J C
JC
González-Sastre
F
F
Blanco-Vaca
F
F
D000818:Animals; D016633:Apolipoprotein A-II / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D003315:Cornea / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D007863:Lecithin Cholesterol Acyltransferase Deficiency / Q000235:genetics / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron
D016633:Apolipoprotein A-II; D008055:Lipids; D008074:Lipoproteins; D002784:Cholesterol