Cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces aortic atherosclerosis in lecithin cholesterol acyltransferase transgenic mice
| Autor: | Robert D. Shamburek, H. Bryan Brewer, Jorge Paiz, Michael Chase, Robert F. Hoyt, Bernhard Föger, Beverly Paigen, Silvia Santamarina-Fojo, Marcelo Amar, Jamila Fruchart-Najib, Christine A. Koch, Boris L. Vaisman |
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| Rok vydání: | 1999 |
| Předmět: |
Genetically modified mouse
medicine.medical_specialty Arteriosclerosis Sterol O-acyltransferase Aortic Diseases Mice Transgenic Biochemistry High cholesterol chemistry.chemical_compound Mice High-density lipoprotein Internal medicine Cholesterylester transfer protein medicine Animals Humans Scavenger receptor Molecular Biology Glycoproteins biology Cholesterol Reverse cholesterol transport Cell Biology medicine.disease Cholesterol Ester Transfer Proteins Mice Inbred C57BL Endocrinology chemistry biology.protein lipids (amino acids peptides and proteins) Female Cholesterol Esters Carrier Proteins Lipoproteins HDL Sterol O-Acyltransferase |
| Zdroj: | The Journal of biological chemistry. 274(52) |
| ISSN: | 0021-9258 |
| Popis: | Expression of human lecithin cholesterol acyltransferase (LCAT) in mice (LCAT-Tg) leads to increased high density lipoprotein (HDL) cholesterol levels but paradoxically, enhanced atherosclerosis. We have hypothesized that the absence of cholesteryl ester transfer protein (CETP) in LCAT-Tg mice facilitates the accumulation of dysfunctional HDL leading to impaired reverse cholesterol transport and the development of a pro-atherogenic state. To test this hypothesis we cross-bred LCAT-Tg with CETP-Tg mice. On both regular chow and high fat, high cholesterol diets, expression of CETP in LCAT-Tg mice reduced total cholesterol (-39% and -13%, respectively; p < 0.05), reflecting a decrease in HDL cholesterol levels. CETP normalized both the plasma clearance of [(3)H]cholesteryl esters ([(3)H]CE) from HDL (fractional catabolic rate in days(-1): LCAT-Tg = 3.7 +/- 0.34, LCATxCETP-Tg = 6.1 +/- 0.16, and controls = 6.4 +/- 0.16) as well as the liver uptake of [(3)H]CE from HDL (LCAT-Tg = 36%, LCATxCETP-Tg = 65%, and controls = 63%) in LCAT-Tg mice. On the pro-atherogenic diet the mean aortic lesion area was reduced by 41% in LCATxCETP-Tg (21.2 +/- 2.0 micrometer(2) x 10(3)) compared with LCAT-Tg mice (35.7 +/- 2.0 micrometer(2) x 10(3); p < 0.001). Adenovirus-mediated expression of scavenger receptor class B (SR-BI) failed to normalize the plasma clearance and liver uptake of [(3)H]CE from LCAT-Tg HDL. Thus, the ability of SR-BI to facilitate the selective uptake of CE from LCAT-Tg HDL is impaired, indicating a potential mechanism leading to impaired reverse cholesterol transport and atherosclerosis in these animals. We conclude that CETP expression reduces atherosclerosis in LCAT-Tg mice by restoring the functional properties of LCAT-Tg mouse HDL and promoting the hepatic uptake of HDL-CE. These findings provide definitive in vivo evidence supporting the proposed anti-atherogenic role of CETP in facilitating HDL-mediated reverse cholesterol transport and demonstrate that CETP expression is beneficial in pro-atherogenic states that result from impaired reverse cholesterol transport. |
| Databáze: | OpenAIRE |
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