Overexpression of human lecithin : cholesterol acyltransferase in mice offers no protection against diet-induced atherosclerosis

Human lecithin:cholesterol acyltransferase (LCAT) is a key enzyme in the me tabolism of cholesterol. We have used homozygous transgenic mice overexpres sing the human LCAT transgene to study the effect of a "Western-type" ather ogenic diet (30% fat, 5% cholesterol and 2% cholic acid) on their LCAT expr ession, activity, lipoprotein profile and tendency to develop atheroscleros is. The LCAT activity was 35-fold higher in serum of the homozygous transge nic mice than in murine control serum, and decreased 11-20% in the transgen ic mice when fed the atherogenic diet. The total cholesterol and high-densi ty lipoprotein cholesterol (HDL-C) concentrations were approximately double d in the transgenic mice compared with the controls when both groups were f ed a regular chow diet. In mice on the atherogenic diet, the triglyceride c oncentration decreased about 50% to the same level in transgenic and contro l mice. Total cholesterol and HDL-C concentrations increased and were 60-80 % higher in the transgenic mice. The expression of LCAT mRNA in the liver w as decreased by 49-60% in the transgenic mice when fed the atherogenic diet . The development of atherosclerosis was similar in transgenic and control mice. Thus, the 14- to 27-fold higher LCAT activity and the higher HDLC con centrations in the homozygous LCAT transgenic mice had no significant prote ctive influence on the development of diet-induced atherosclerosis.