TISSUE-SPECIFIC EXPRESSION OF THE HUMAN GENE FOR LECITHIN-CHOLESTEROLACYLTRANSFERASE IN TRANSGENIC MICE ALTERS BLOOD-LIPIDS, LIPOPROTEINS AND LIPASES TOWARDS A LESS ATHEROGENIC PROFILE

Lecithin:cholesterol acyltransferase (LCAT) is a key enzyme in the rev erse cholesterol pathway but its role in lipid metabolism is still unc lear. We have generated mice transgenic for a 7-kb genomic DNA fragmen t comprising the 6 exons and 5 introns of the LCAT gene with 1932 bp o f 5' flanking and 908 bp of 3' flanking sequences. One line had integr ated about 30 copies and expressed about 40-fold increased LCAT activi ty in a human test system. The expression showed correct tissue specif icity of the human LCAT gene. Increased LCAT activity resulted in a de crease of plasma triacylglycerols below 50% of fasting controls. This reduction was seen in all Lipoprotein fractions. Lipoprotein lipase ac tivity did not change significantly, whereas hepatic triacylglycerol l ipase increased markedly. Plasma total cholesterol was similar in fast ing transgenic and control mice, but low-density lipoprotein and very low-density lipoprotein cholesterol were reduced to about 50%. High-de nsity lipoprotein cholesterol increased about 20%, accompanied by a co rrespondingly increased size and a higher cholesterol efflux-stimulati ng activity of transgenic LCAT high-density lipoprotein. Both apolipop rotein A-I and A-II plasma concentrations increased in transgenic mice . Plasma triacylglycerol and cholesteryl ester fatty acid distribution showed an increased proportion of palmitic acid, whereas oleic, linol eic and arachidonic acid decreased, thus resembling more closely the h uman situation. Overexpression of the human LCAT gene provokes major c hanges in plasma lipoprotein and apolipoprotein concentrations, result ing in a less atherogenic plasma lipoprotein profile through a reducti on in atherogenic and an increase in anti-atherogenic lipoproteins.