title: Lack of acyl-CoA:diacylglycerol acyltransferase 1 reduces intestinal cholesterol absorption and attenuates atherosclerosis in apolipoprotein E knockout mice.
abstract: Triacylglycerols (TG) are the major storage molecules of metabolic energy and fatty acids in several tissues. The final step in TG biosynthesis is catalyzed by acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes. Lack of whole body DGAT1 is associated with reduced lipid-induced inflammation. Since one major component of atherosclerosis is chronic inflammation we hypothesized that DGAT1 deficiency might ameliorate atherosclerotic lesion development. We therefore crossbred Apolipoprotein E-deficient (ApoE(-/-)) mice with Dgat1(-/-) mice. ApoE(-/-) and ApoE(-/-)Dgat1(-/-) mice were fed Western-type diet (WTD) for 9weeks and thereafter examined for plaque formation. The mean atherosclerotic lesion area was substantially reduced in ApoE(-/-)Dgat1(-/-) compared with ApoE(-/-) mice in en face and aortic valve section analyses. The reduced lesion size was associated with decreased cholesterol uptake and absorption by the intestine, reduced plasma TG and cholesterol concentrations and increased cholesterol efflux from macrophages. The expression of adhesion molecules was reduced in aortas of ApoE(-/-)Dgat1(-/-) mice, which might be the reason for less migration capacities of monocytes and macrophages and the observed decreased amount of macrophages within the plaques. From our results we conclude that the lack of DGAT1 is atheroprotective, implicating an additional application of DGAT1 inhibitors with regard to maintaining cholesterol homeostasis and attenuating atherosclerosis.
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21, Graz, Austria.
authors.forename: Prakash G
authors.initials: PG
authors.lastname: Chandak
authors.forename: Sascha
authors.initials: S
authors.lastname: Obrowsky
authors.forename: Branislav
authors.initials: B
authors.lastname: Radovic
authors.forename: Prakash
authors.initials: P
authors.lastname: Doddapattar
authors.forename: Elma
authors.initials: E
authors.lastname: Aflaki
authors.forename: Adelheid
authors.initials: A
authors.lastname: Kratzer
authors.forename: Lalit S
authors.initials: LS
authors.lastname: Doshi
authors.forename: Silvia
authors.initials: S
authors.lastname: Povoden
authors.forename: Helmut
authors.initials: H
authors.lastname: Ahammer
authors.forename: Gerald
authors.initials: G
authors.lastname: Hoefler
authors.forename: Sanja
authors.initials: S
authors.lastname: Levak-Frank
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
mesh_terms: D000214:Acyl Coenzyme A / Q000097:blood; D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000201:enzymology / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood*; D003433:Crosses, Genetic; D051048:Diacylglycerol O-Acyltransferase / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007408:Intestinal Absorption / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000097:blood* / Q000473:pathology; D014280:Triglycerides / Q000097:blood*
chemical_list: D000214:Acyl Coenzyme A; D001057:Apolipoproteins E; D014280:Triglycerides; D002784:Cholesterol; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase