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 generated in a reaction catalyzed by acyl CoA:cholesterol acyltransferase (ACAT). To examine the effect of cholesteryl esters on the secretion of apoB-containing lipoproteins, we transiently overexpressed human (h) ACAT-1 in the livers of low density lipoprotein (LDL) receptor(-/-) mice using adenovirus-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. Overexpression of hACAT-1 markedly increased the plasma concentration and hepatic secretion of apoB-containing lipoproteins but had no effect on the clearance of very low density lipoprotein-apoB from plasma indicating that cholesteryl esters play an important role in regulating the assembly and secretion 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 feeds back on LDL receptor expression. We directly tested this hypothesis in hamsters by transiently overexpressing hACAT-1 in the liver. Enhanced cholesterol esterification in the liver resulted in a compensatory increase in de novo cholesterol synthesis but no induction of LDL receptor expression suggesting that fatty acids regulate LDL receptor expression via a mechanism independent of ACAT.
Spady
D K
DK
Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. spady@utsw.swmed.edu
Willard
M N
MN
Meidell
R S
RS
D000818:Animals; D002788:Cholesterol Esters / Q000378:metabolism; D006224:Cricetinae; D006801:Humans; D008079:Lipoproteins, VLDL / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008647:Mesocricetus; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D002785:Sterol O-Acyltransferase / Q000378:metabolism*
D002788:Cholesterol Esters; D008079:Lipoproteins, VLDL; D011973:Receptors, LDL; D002785:Sterol O-Acyltransferase