Role of acyl-coenzyme A : cholesterol acyltransferase-1 in the control of hepatic very low density lipoprotein secretion and low density lipoprotein receptor expression in the mouse and hamster

Cholesteryl esters present in nascent very low density lipoproteins are gen erated in a reaction catalyzed by acyl CoA:cholesterol acyltransferase (ACA T), To examine the effect of cholesteryl esters on the secretion of apoB-co ntaining lipoproteins, we transiently overexpressed human (h) ACAT-1 in the livers of low density lipoprotein (LDL) receptor(-/-) mice using adenoviru s-mediated gene transfer. Overexpression of hACAT-1 increased hepatic total and esterified cholesterol but did not reduce hepatic free cholesterol due to a compensatory increase in the rate of de novo cholesterol synthesis. O verexpression of hACAT-1 markedly increased the plasma concentration and he patic secretion of apoB-containing lipoproteins but had no effect on the cl earance of very low density lipoprotein-apoB from plasma indicating that ch olesteryl esters play an important role in regulating the assembly and secr etion of apoB-containing lipoproteins. ACAT activity has been implicated in the regulation of the LDL receptor pathway by dietary fatty acids. it has been hypothesized that unsaturated fatty acids, by enhancing ACAT activity, reduce the amount of free cholesterol in a putative regulatory pool that f eeds back on LDL receptor expression. We directly tested this hypothesis in hamsters by transiently overexpressing hACAT-1 in the liver. Enhanced chol esterol esterification in the liver resulted in a compensatory increase in de novo cholesterol synthesis but no induction of LDL receptor expression s uggesting that fatty acids regulate LDL receptor expression via a mechanism independent of ACAT.