Lack of acyl-CoA:diacylglycerol acyltransferase 1 reduces intestinal cholesterol absorption and attenuates atherosclerosis in apolipoprotein E knockout mice
| Autor: | Lalit S. Doshi, Branislav Radovic, Dagmar Kratky, Prakash G. Chandak, Gerald Hoefler, Adelheid Kratzer, Elma Aflaki, Silvia Povoden, Sascha Obrowsky, Sanja Levak-Frank, Prakash Doddapattar, Helmut Ahammer |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Apolipoprotein E
Apolipoprotein B 030204 cardiovascular system & hematology Intestinal absorption chemistry.chemical_compound Mice 0302 clinical medicine Cell Movement FFA free fatty acids Cholesterol absorption Cholesterol efflux Intestinal Mucosa Aorta Cells Cultured ApoE apolipoprotein E 2. Zero hunger Mice Knockout 0303 health sciences biology DGAT acyl-CoA:diacylglycerol acyltransferase Immunohistochemistry Plaque Atherosclerotic TG triacylglycerol Acyl-CoA:diacylglycerol acyltransferase 1 Cholesterol Intestinal cholesterol absorption lipids (amino acids peptides and proteins) Female medicine.symptom FC free cholesterol medicine.medical_specialty Inflammation Article Lesion 03 medical and health sciences Acyl-CoA Apolipoproteins E Internal medicine medicine Animals Humans Diacylglycerol O-Acyltransferase Molecular Biology Crosses Genetic Triglycerides 030304 developmental biology Macrophages Cell Biology Atherosclerosis Lipid Metabolism TC total cholesterol Apolipoprotein E knockout mice Disease Models Animal Endocrinology chemistry WTD western-type diet Intestinal Absorption FA fatty acids biology.protein Acyl Coenzyme A |
| Zdroj: | Biochimica et Biophysica Acta |
| ISSN: | 0006-3002 |
| Popis: | 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 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. Graphical abstract Highlights ► DGAT1 deficiency on an ApoE-null background reduces diet-induced atherosclerotic lesion formation. ► DGAT1 deficiency decreases cholesterol uptake and absorption in ApoE-null mice. ► Reduced macrophage migration and decreased aortic inflammation in ApoE-null mice lacking DGAT1. ► Increased cholesterol efflux from macrophages lacking DGAT1. ► Additional potential application of DGAT1 inhibitors with regard to attenuating atherosclerosis. |
| Databáze: | OpenAIRE |
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