Cholesterol esterification by ACAT2 is essential for efficient intestinal cholesterol absorption: evidence from thoracic lymph duct cannulation

The hypothesis tested in this study was that cholesterol esterification by ACAT2 would increase cholesterol absorption efficiency by providing cholesteryl ester (CE) for incorporation into chylomicrons. The assumption was that absorption would be proportional to Acat2 gene dosage. Male ACAT2+/+, ACAT2+/−, and ACAT2−/− mice were fed a diet containing 20% of energy as palm oil with 0.2% (w/w) cholesterol. Cholesterol absorption efficiency was measured by fecal dual-isotope and thoracic lymph duct cannulation (TLDC) methods using [3H]sitosterol and [14C]cholesterol tracers. Excellent agreement among individual mice was found for cholesterol absorption measured by both techniques. Cholesterol absorption efficiency in ACAT2−/− mice was 16% compared with 46–47% in ACAT2+/+ and ACAT2+/− mice. Chylomicrons from ACAT2+/+ and ACAT2+/− mice carried ∼80% of total sterol mass as CE, whereas ACAT2−/− chylomicrons carried >90% of sterol mass in the unesterified form. The total percentage of chylomicron mass as CE was reduced from 12% in the presence of ACAT2 to ∼1% in ACAT2−/− mice. Altogether, the data demonstrate that ACAT2 increases cholesterol absorption efficiency by providing CE for chylomicron transport, but one copy of the Acat2 gene, providing ∼50% of ACAT2 mRNA and enzyme activity, was as effective as two copies in promoting cholesterol absorption. The hypothesis tested in this study was that cholesterol esterification by ACAT2 would increase cholesterol absorption efficiency by providing cholesteryl ester (CE) for incorporation into chylomicrons. The assumption was that absorption would be proportional to Acat2 gene dosage. Male ACAT2+/+, ACAT2+/−, and ACAT2−/− mice were fed a diet containing 20% of energy as palm oil with 0.2% (w/w) cholesterol. Cholesterol absorption efficiency was measured by fecal dual-isotope and thoracic lymph duct cannulation (TLDC) methods using [3H]sitosterol and [14C]cholesterol tracers. Excellent agreement among individual mice was found for cholesterol absorption measured by both techniques. Cholesterol absorption efficiency in ACAT2−/− mice was 16% compared with 46–47% in ACAT2+/+ and ACAT2+/− mice. Chylomicrons from ACAT2+/+ and ACAT2+/− mice carried ∼80% of total sterol mass as CE, whereas ACAT2−/− chylomicrons carried >90% of sterol mass in the unesterified form. The total percentage of chylomicron mass as CE was reduced from 12% in the presence of ACAT2 to ∼1% in ACAT2−/− mice. Altogether, the data demonstrate that ACAT2 increases cholesterol absorption efficiency by providing CE for chylomicron transport, but one copy of the Acat2 gene, providing ∼50% of ACAT2 mRNA and enzyme activity, was as effective as two copies in promoting cholesterol absorption. Elevated plasma cholesterol concentration is widely accepted as a risk factor for accelerated atherosclerosis and coronary heart disease (CHD) (1.Rosamond W. Flegal K. Furie K. Go A. Greenlund K. Haase N. 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CE is in and be into lipid into the of lipoprotein for of the that in intestinal CE in ACAT2+/− ACAT2−/− mice be with cholesterol absorption and that as the copy of ACAT2 a in cholesterol absorption efficiency would of cholesterol absorption, a of thoracic lymph duct cannulation (TLDC) was in mice to the mechanisms of newly absorbed cholesterol is transported and into the via lipoproteins, chylomicrons. documented by and in absorption, and in and as by the and a J. 34: Scopus Google Scholar), chylomicron in thoracic duct lymph of humans and various animal are the of dietary were to that lymph from the and the of the into the the the thoracic duct and the the have to thoracic duct lymph during lipid absorption in mice to the mechanisms of a of intestinal cholesterol absorption and The in this study was by et M. Novak S. R.S. R.L. Turley S. to and in Med. 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ACAT2−/− mice a in plasma cholesterol concentration to that in ACAT2+/+ and ACAT2+/− mice. were to expression of ACAT2 enzyme in of and compared with that of the liver The data that of ACAT2 enzyme in the of the and that this was in of the in the to ACAT1 enzyme was one that of ACAT2 in both the and in the liver ACAT1 was in ACAT2−/− mice as in ACAT2+/+ and ACAT2+/− mice. ACAT2+/− mice ∼50% ACAT2 ACAT2+/+ mice in of the and in the whereas was in from ACAT2−/− mice. ACAT2 mRNA expression the gene as ACAT2 Acat2 gene expression was ∼50% in ACAT2+/− ACAT2+/+ and was in ACAT2−/− mice. the of ACAT2 mRNA the of the was different from the of enzyme activity, with of mRNA enzyme expression was measured for and mRNA expression was in expression was in of ACAT2−/− mice compared with with functional the gene was as were ACAT2+/+ and ACAT2+/− mice. The of expression in was to that of Acat2 and in of the expression was in the of the in ACAT2−/− mice. data were in agreement with data J.M. 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[3H]sitosterol absorption of the in lymph the and of ACAT2 gene was were the of [14C]cholesterol in lymph and and to and in ACAT2+/+, ACAT2+/−, and ACAT2−/− the of The percentage of [3H]sitosterol absorption to in of mice The were lymph of to in of in lymph mass to be in the were found among the the of lymph of the total was found in the plasma and liver of that the in the and that a of newly absorbed cholesterol. that to cholesterol absorption as by M.D. Rudel L.L. Intestinal cholesterol absorption is reduced in mice in both and Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, J. C. J.M. N. B. et to in Clin. Invest. PubMed Scopus Google Scholar, S.D. J.M. mechanisms the of unesterified cholesterol in the of mice in both ACAT2 and J. Physiol. Physiol. PubMed Scopus Google Scholar). in the as the the and the lymph was to study the of chylomicrons that are newly absorbed cholesterol. this the into lymph during absorption of from the ACAT2 enzyme the percentage of chylomicron into sterol was found and of [14C]cholesterol in ACAT2+/+ and ACAT2+/− in the ester whereas ACAT2−/− chylomicrons carried in the unesterified form The of sterol ester in the that have by the of ACAT2−/− mice is have from but this as ACAT1 found in the Rudel L.L. expression of ACAT1 and ACAT2 among and of nonhuman Lipid Res. 41: Full Text Full Text PDF PubMed Google Scholar). have from the by et M. S.L. of two human of the acyltransferase gene Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the with this The percentage of [3H]sitosterol was and in ACAT2+/+ and ACAT2+/− whereas was in ACAT2−/− chylomicrons data the that ACAT2 cholesterol as Rudel L.L. with acyl-CoA:cholesterol and ACAT2 the to cholesterol from Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). were in the of chylomicron mass mass to be in ACAT2−/− mice in of the total mass in chylomicrons from The was that ACAT2−/− mice CE into chylomicrons ACAT2+/+ and ACAT2+/− CE and that CE in chylomicrons from cholesterol of chylomicron to of cholesterol and cholesterol ester (CE) was measured in chylomicrons from The was by mass by the of for chylomicron from The percentage of from animal was for The data are the for The was by the of and by the of and the as measured by and in a new of cholesterol and cholesterol ester (CE) was measured in chylomicrons from The was by mass by the of for chylomicron from The percentage of from animal was for The data are the for The was by the of and by the of and the as measured by and and chylomicron were was in the of The percentage of chylomicron mass as CE was reduced from and in ACAT2+/+ and ACAT2+/−, to in ACAT2−/− this was for by increase in as the percentage of total to mass and the percentage of were in was but were found in among individual in the percentage of from individual the were found the in chylomicrons to from nonhuman R.L. Rudel L.L. Effect of dietary cholesterol the of thoracic duct lymph lipoproteins from nonhuman Lipid Res. 1983; 24: Full Text PDF PubMed Google and K. Fainaru M. Havel R.J. Composition of proteins of mesenteric lymph chylomicrons in the rat and alterations produced upon exposure of chylomicrons to blood serum and serum proteins.J. Lipid Res. 1978; 19: 712-722Abstract Full Text PDF PubMed Google Scholar), with the of of chylomicron of chylomicron proteins were and for of were by are in a new chylomicron proteins were and for of were by are study new a for ACAT2 in intestinal cholesterol absorption and transport in chylomicrons. The of thoracic duct lymph during absorption of a in cholesterol absorption CE incorporation into whereas the of newly absorbed cholesterol the into is from a of cholesterol during absorption of a the of ACAT2 the of cholesterol absorption. data and chylomicron sterol mass that CE chylomicron for cholesterol transport of the into lymph and that the of cholesterol esterification by ACAT2 is with cholesterol absorption. our demonstrate in the ACAT2 is the enzyme for cholesterol that cholesterol esterification by ACAT2 cholesterol absorption the of absorption would be proportional to Acat2 gene dosage. this was as the ACAT2+/− mice the absorption efficiency as the ACAT2+/+ mice. Intestinal ACAT2 is in in and the of ACAT2 in the is to provide for cholesterol esterification and absorption. our mRNA the of Acat2 in the to be with a of expression, a in agreement with data M.D. Rudel L.L. Intestinal cholesterol absorption is reduced in mice in both and Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, J.M. Turley S.D. ACAT2 cholesterol absorption in the PubMed Scopus Google Scholar, S.D. J.M. mechanisms the of unesterified cholesterol in the of mice in both ACAT2 and J. Physiol. Physiol. PubMed Scopus Google Scholar, M. J. et is the intestinal and cholesterol and a of cholesterol Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). in of the have to the in cholesterol absorption efficiency in ACAT2−/− mice by the of cholesterol into the but is the in expression would be a a to the cholesterol absorption ACAT2−/− mice a of mRNA expression via liver that excretion of of the and into the of the is a factor that cholesterol absorption. the of chylomicron to be and and gene expression the of the were agreement with M.D. Rudel L.L. Intestinal cholesterol absorption is reduced in mice in both and Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, S.D. J.M. mechanisms the of unesterified cholesterol in the of mice in both ACAT2 and J. Physiol. Physiol. PubMed Scopus Google Scholar), mRNA expression to be in ACAT2−/− mice compared with mice with this increase was and was in and mRNA to be in and of the ACAT2+/− a that was in measurement in ACAT2+/− mice. the that of were in the plasma and in the liver thoracic duct lymph that of unesterified cholesterol via the of the was a factor cholesterol absorption The mRNA of cholesterol as and were very low and different among The low that to the dietary cholesterol this the cholesterol absorption that were to from the cholesterol absorption by sterol excretion into The of is that newly absorbed in the lymph can be a and lipoproteins by the can be in as in this one to lymph from the thoracic lymph is the for lymph the for a of intestinal were to to the risk for the with the and to to the a for and for and the mice were to to lymph was to the of and to lymph The functional the of the as by the that lymph and chylomicron studies were in the mice a containing 20% of energy as fat and 0.2% cholesterol, a diet in have documented a for ACAT2 in atherosclerosis T.A. J.M. K.M. Rudel L.L. of acyl-coenzyme acyltransferase with atherosclerosis in lipoprotein Biol. PubMed Scopus Google Scholar). the of the of the total was found in the plasma and the liver of that of newly absorbed cholesterol from the intestinal the via as have M.D. Rudel L.L. Intestinal cholesterol absorption is reduced in mice in both and Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, J. C. J.M. N. B. et to in Clin. Invest. PubMed Scopus Google Scholar, K. of intestinal Lipid Res. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). our data that cholesterol absorption CE incorporation into chylomicron are transported via the the blood the et J. C. J.M. N. B. et to in Clin. Invest. PubMed Scopus Google compared plasma in mice to and that the of the plasma that are into the but into the mesenteric lymph duct cannulation revealed of [14C]cholesterol in from data would with the that newly absorbed cholesterol is into for into our data that synthesis by the is a for dietary cholesterol absorption, as found of cholesterol in the plasma and the liver of our mice of thoracic lymph duct the of chylomicron by as well as by lipid and of [14C]cholesterol and [3H]sitosterol into sterol the that ACAT2 cholesterol by studies Rudel L.L. with acyl-CoA:cholesterol and ACAT2 the to cholesterol from Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, esterification by intestinal A:cholesterol acyltransferase (ACAT) and cholesterol Lipid Res. 1983; 24: Full Text PDF PubMed Google Scholar). the chylomicron and the were the the chylomicron was of CE ACAT2 was by chylomicrons by ACAT2+/+ and ACAT2+/− mice both and the of of the exogenous cholesterol into the as that is into the of the chylomicron among to a in the was of that the in of this in chylomicron in ACAT2−/− the percentage cholesterol absorption into lymph is and with chylomicron CE mass have that of CE would in reduced cholesterol absorption, but this study is the to that CE by ACAT2 chylomicron for transport of newly absorbed cholesterol of the into the and into the Altogether, studies provide a of to the hypothesis that the presence of ACAT2 cholesterol absorption efficiency by providing CE for incorporation into chylomicron the data in the ACAT2+/− mice that ACAT2 mice have of ACAT2 enzyme to the ACAT2 and mice both and absorbed a of exogenous cholesterol. that the of intestinal cholesterol absorption by ACAT2 to cholesterol from the and preventing atherosclerosis but a of ACAT2 to in of cholesterol absorption. studies are to molecular mechanisms that in intestinal cholesterol absorption, by with The and for to the of L. and our was in this with cholesterol ester coronary heart disease cardiovascular disease cholesterol fecal dual-isotope high density lipoprotein cholesterol low density lipoprotein cholesterol thoracic lymph duct cannulation total plasma cholesterol very low density lipoprotein cholesterol

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