MICE OVEREXPRESSING HUMAN LECITHIN - CHOLESTEROL ACYLTRANSFERASE ARE NOT PROTECTED AGAINST DIET-INDUCED ATHEROSCLEROSIS

Lecithin: cholesterol acyltransferase (LCAT)(EC 2.3.1.43) is generally assumed to participate in reverse cholesterol transport, i.e., choles terol transport from peripheral tissues to the liver. LCAT is secreted by the liver and transported in plasma mostly associated with high de nsity lipoprotein. It catalyzes the esterification of cholesterol, mai nly high density lipoprotein cholesterol, and produces cholesteryl est er and lysolecithin. Transgenic mice overexpressing human LCAT on a C5 7BL/6 background have elevated high density lipoprotein cholesterol an d markedly reduced low and very low density lipoprotein cholesterol an d triglyceride levels in plasma, suggesting that such mice may be less susceptible to diet-induced atherosclerosis than isogenic nontransgen ic controls. To determine if the apparent anti-atherogenic lipoprotein profile of the LCAT transgenics reduced their susceptibility to ather ogenesis, the atherosclerotic lesions developing in transgenic LCAT mi ce and controls when fed an atherogenic diet were compared by histolog y and morphometry. Histological examination of the aortas from mice fe d a high fat diet for 12, 17 and 22 weeks revealed that the aortic les ions were no smaller or less developed in the transgenic LCAT mice tha n in the C57BL/6 controls. After 17 weeks there were significantly mor e ''fatty streaks'' in the transgenic mice than in the controls. Thus, overexpression of human LCAT in transgenic mice, in spite of their ve ry favourable blood lipoprotein and lipid profile, does not protect ag ainst development of atherosclerosis.