Inhibition of lecithin:Cholesterol acyltransferase following intravenous administration of heparin in man

Abstract

1. 1. Lecithin:cholesterol acyltransferase (EC 2.3.1.43) is the enzyme responsible for the esterification of free cholesterol in human plasma. A marked decrease in the initial rate of enzyme activity was observed in the sera of subjects who received 5000 units of heparin intravenously 4 h after a 1200 calorie meal. This inhibition occurred coincident in time with a marked elevation of serum free fatty acid concentration. Both of these effects could be observed as early as I min following heparin administration. 2. 2. When heparin was given to subjects in the fasting state, the inhibition of enzyme activity was seen only in subjects whose serum triglyceride levels were sufficiently high to produce free fatty acid concentrations in excess of 1000 μequiv/1. 3. 3. In vitro addition of free fatty acids (in the form of palmitic acid) and lysolecithin to the reaction mix separately and together also resulted in reduced enzyme activity which could in turn be reversed by increasing amounts of serum albumin. The data are consistent with the presence of multiple sites for the binding of free fatty acids and lysolecithin by serum albumin: One site binds up to 2 moles of free fatty acids per mole of albumin. The excess free fatty acids compete with lysolecithin for a second site, the binding capacity of the lysolecithin being approx. I mole of lysolecithin per mole of serum albumin. Thus, lecithin:cholesterol acyltransferase inhibition may be caused by a combination of elevated free fatty acids and unbound lysolecithin, the latter being a product of the lecithin:cholesterol acyltransferase reaction which apparently cannot be removed from the enzyme surface when free fatty acids already occupy lysolecithin binding sites on serum albumin.