Lack of acyl-CoA:diacylglycerol acyltransferase 1 reduces intestinal cholesterol absorption and attenuates atherosclerosis in apolipoprotein E knockout mice

被引:28
作者
Chandak, Prakash G. [1 ]
Obrowsky, Sascha [1 ]
Radovic, Branislav [1 ]
Doddapattar, Prakash [1 ]
Aflaki, Elma [1 ]
Kratzer, Adelheid [1 ]
Doshi, Lalit S. [1 ]
Povoden, Silvia [1 ]
Ahammer, Helmut [2 ]
Hoefler, Gerald [3 ]
Levak-Frank, Sanja [1 ]
Kratky, Dagmar [1 ]
机构
[1] Med Univ Graz, Inst Mol Biol & Biochem, Ctr Mol Med, A-8010 Graz, Austria
[2] Med Univ Graz, Inst Biophys, A-8010 Graz, Austria
[3] Med Univ Graz, Inst Pathol, A-8036 Graz, Austria
来源
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS | 2011年 / 1811卷 / 12期
基金
奥地利科学基金会;
关键词
Atherosclerosis; Cholesterol absorption; Cholesterol efflux; Acyl-CoA:diacylglycerol acyltransferase 1; Inflammation; Apolipoprotein E knockout mice; DIACYLGLYCEROL ACYLTRANSFERASE; HEPATIC STEATOSIS; INTEGRIN VLA-4; OBESITY; HYPERCHOLESTEROLEMIA; INFLAMMATION; DGAT1; DEFICIENCY; METABOLISM; MECHANISMS;
D O I
10.1016/j.bbalip.2011.08.010
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 9 weeks and thereafter examined for plaque formation. The mean atherosclerotic lesion area was substantially reduced in ApoE(-/-)Dgat1(-/-) compared with ApoE(-/-) mice in enlace 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. (C) 2011 Elsevier B.V. All rights reserved.
引用
收藏
页码:1011 / 1020
页数:10
相关论文
共 29 条
[1]   THE INTEGRIN VLA-4 SUPPORTS TETHERING AND ROLLING IN FLOW ON VCAM-1 [J].
ALON, R ;
KASSNER, PD ;
CARR, MW ;
FINGER, EB ;
HEMLER, ME ;
SPRINGER, TA .
JOURNAL OF CELL BIOLOGY, 1995, 128 (06) :1243-1253
[2]   DEGRADATION OF CATIONIZED LOW-DENSITY LIPOPROTEIN AND REGULATION OF CHOLESTEROL-METABOLISM IN HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA FIBROBLASTS [J].
BASU, SK ;
GOLDSTEIN, JL ;
ANDERSON, RGW ;
BROWN, MS .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1976, 73 (09) :3178-3182
[3]   Discovery of a Potent, Selective, and Orally Efficacious Pyrimidinooxazinyl Bicyclooctaneacetic Acid Diacylglycerol Acyltransferase-1 Inhibitor [J].
Birch, Alan M. ;
Birtles, Susan ;
Buckett, Linda K. ;
Kemmitt, Paul D. ;
Smith, Graham J. ;
Smith, Tim J. D. ;
Turnbull, Andrew V. ;
Wang, Steven J. Y. .
JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (06) :1558-1568
[4]   Intestinal ABCA1 directly contributes to HDL biogenesis in vivo [J].
Brunham, LR ;
Kruit, JK ;
Iqbal, J ;
Fievet, C ;
Timmins, JM ;
Pape, TD ;
Coburn, BA ;
Bissada, N ;
Staels, B ;
Groen, AK ;
Hussain, MM ;
Parks, JS ;
Kuipers, F ;
Hayden, MR .
JOURNAL OF CLINICAL INVESTIGATION, 2006, 116 (04) :1052-1062
[5]   DGAT1 is not essential for intestinal triacylglycerol absorption or chylomicron synthesis [J].
Buhman, KK ;
Smith, SJ ;
Stone, SJ ;
Repa, JJ ;
Wong, JS ;
Knapp, FF ;
Burri, BJ ;
Hamilton, RL ;
Abumrad, NA ;
Farese, RV .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (28) :25474-25479
[6]   Effects of sex and age on atherosclerosis and autoimmunity in apoE-deficient mice [J].
Caligiuri, G ;
Nicoletti, A ;
Zhou, XH ;
Törnberg, I ;
Hansson, GK .
ATHEROSCLEROSIS, 1999, 145 (02) :301-308
[7]   Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis [J].
Cases, S ;
Smith, SJ ;
Zheng, YW ;
Myers, HM ;
Lear, SR ;
Sande, E ;
Novak, S ;
Collins, C ;
Welch, CB ;
Lusis, AJ ;
Erickson, SK ;
Farese, RV .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (22) :13018-13023
[8]   Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members [J].
Cases, S ;
Stone, SJ ;
Zhou, P ;
Yen, E ;
Tow, B ;
Lardizabal, KD ;
Voelker, T ;
Farese, RV .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (42) :38870-38876
[9]   Efficient Phagocytosis Requires Triacylglycerol Hydrolysis by Adipose Triglyceride Lipase [J].
Chandak, Prakash G. ;
Radovic, Branislav ;
Aflaki, Elma ;
Kolb, Dagmar ;
Buchebner, Marlene ;
Froehlich, Eleonore ;
Magnes, Christoph ;
Sinner, Frank ;
Haemmerle, Guenter ;
Zechner, Rudolf ;
Tabas, Ira ;
Levak-Frank, Sanja ;
Kratky, Dagmar .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (26) :20192-20201
[10]   Deficiency of Niemann-Pick C1 like 1 prevents atherosclerosis in ApoE-/- mice [J].
Davis, Harry R., Jr. ;
Hoos, Lizbeth M. ;
Tetzloff, Glen ;
Maguire, Maureen ;
Zhu, Li-ji ;
Graziano, Michael P. ;
Altmann, Scott W. .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2007, 27 (04) :841-849