Paradoxical effect on atherosclerosis of hormone-sensitive lipase overexpression in macrophages
Foam cells formed from receptor-mediated uptake of lipoprotein cholesterol by macrophages in the arterial intima are critical in the initiation, progression, and stability of atherosclerotic lesions. Macrophages accumulate cholesterol when conditions favor esterification by acyl-CoA:cholesterol acyl...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
1999-03-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520324433 |
| _version_ | 1818647217464934400 |
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| author | Jean-Louis Escary Henry A. Choy Karen Reue Xu-Ping Wang Lawrence W. Castellani Christopher K. Glass Aldons J. Lusis Michael C. Schotz |
| author_facet | Jean-Louis Escary Henry A. Choy Karen Reue Xu-Ping Wang Lawrence W. Castellani Christopher K. Glass Aldons J. Lusis Michael C. Schotz |
| author_sort | Jean-Louis Escary |
| collection | DOAJ |
| description | Foam cells formed from receptor-mediated uptake of lipoprotein cholesterol by macrophages in the arterial intima are critical in the initiation, progression, and stability of atherosclerotic lesions. Macrophages accumulate cholesterol when conditions favor esterification by acyl-CoA:cholesterol acyltransferase (ACAT) over cholesterylester hydrolysis by a neutral cholesteryl-ester hydrolase, such as hormone-sensitive lipase (HSL), and subsequent cholesterol efflux mediated by extracellular acceptors. We recently made stable transfectants of a murine macrophage cell line, RAW 264.7, that overexpressed a rat HSL cDNA and had a 5-fold higher rate of cholesteryl-ester hydrolysis than control cells. The current study examined the effect of macrophage-specific HSL overexpression on susceptibility to diet-induced atherosclerosis in mice. A transgenic line overexpressing the rat HSL cDNA regulated with a macrophage-specific scavenger receptor promoter-enhancer was established by breeding with C57BL/6J mice. Transgenic peritoneal macrophages exhibited macrophage-specific 7-fold overexpression of HSL cholesterol esterase activity. Total plasma cholesterol levels in transgenic mice fed a chow diet were modestly elevated 16% compared to control littermates. After 14 weeks on a high-fat, high-cholesterol diet, total cholesterol increased 3-fold, with no difference between transgenics and controls. However, HSL overexpression resulted in thicker aortic fatty lesions that were 2.5-times larger in transgenic mice. HSL expression in the aortic lesions was shown by immunocytochemistry. Atherosclerosis was more advanced in transgenic mice exhibiting raised lesions involving the aortic wall, along with lipid accumulation in coronary arteries occurring only in transgenics. Thus, increasing cholesteryl-ester hydrolysis, without concomitantly decreasing ACAT activity or increasing cholesterol efflux, is not sufficient to protect against atherosclerosis.—Escary, J-L., H. A. Choy, K. Reue, X-P. Wang, L. W. Castellani, C. K. Glass, A. J. Lusis, and M. C. Schotz. Paradoxical effect on atherosclerosis of hormone-sensitive lipase overexpression in macrophages. J. Lipid Res. 1999. 40: 397–404. |
| first_indexed | 2024-12-17T00:59:01Z |
| format | Article |
| id | doaj.art-49376936a7764534a7790ec4d72423aa |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-17T00:59:01Z |
| publishDate | 1999-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-49376936a7764534a7790ec4d72423aa2022-12-21T22:09:31ZengElsevierJournal of Lipid Research0022-22751999-03-01403397404Paradoxical effect on atherosclerosis of hormone-sensitive lipase overexpression in macrophagesJean-Louis Escary0Henry A. Choy1Karen Reue2Xu-Ping Wang3Lawrence W. Castellani4Christopher K. Glass5Aldons J. Lusis6Michael C. Schotz7Lipid Research Laboratory, West Los Angeles VA Medical Center, Los Angeles, CA 90073; Department of Medicine, Molecular Biology Institute, University of California, Los Angeles, CA 90095Lipid Research Laboratory, West Los Angeles VA Medical Center, Los Angeles, CA 90073; Department of Medicine, Molecular Biology Institute, University of California, Los Angeles, CA 90095Lipid Research Laboratory, West Los Angeles VA Medical Center, Los Angeles, CA 90073; Department of Medicine, Molecular Biology Institute, University of California, Los Angeles, CA 90095Department of Medicine, Molecular Biology Institute, University of California, Los Angeles, CA 90095Department of Medicine, Molecular Biology Institute, University of California, Los Angeles, CA 90095Department of Medicine, University of California, San Diego, La Jolla, CA 92093Department of Medicine, Molecular Biology Institute, University of California, Los Angeles, CA 90095; Department of Microbiology and Molecular Genetics, Molecular Biology Institute, University of California, Los Angeles, CA 90095To whom correspondence should be addressed.; Lipid Research Laboratory, West Los Angeles VA Medical Center, Los Angeles, CA 90073; Department of Medicine, Molecular Biology Institute, University of California, Los Angeles, CA 90095Foam cells formed from receptor-mediated uptake of lipoprotein cholesterol by macrophages in the arterial intima are critical in the initiation, progression, and stability of atherosclerotic lesions. Macrophages accumulate cholesterol when conditions favor esterification by acyl-CoA:cholesterol acyltransferase (ACAT) over cholesterylester hydrolysis by a neutral cholesteryl-ester hydrolase, such as hormone-sensitive lipase (HSL), and subsequent cholesterol efflux mediated by extracellular acceptors. We recently made stable transfectants of a murine macrophage cell line, RAW 264.7, that overexpressed a rat HSL cDNA and had a 5-fold higher rate of cholesteryl-ester hydrolysis than control cells. The current study examined the effect of macrophage-specific HSL overexpression on susceptibility to diet-induced atherosclerosis in mice. A transgenic line overexpressing the rat HSL cDNA regulated with a macrophage-specific scavenger receptor promoter-enhancer was established by breeding with C57BL/6J mice. Transgenic peritoneal macrophages exhibited macrophage-specific 7-fold overexpression of HSL cholesterol esterase activity. Total plasma cholesterol levels in transgenic mice fed a chow diet were modestly elevated 16% compared to control littermates. After 14 weeks on a high-fat, high-cholesterol diet, total cholesterol increased 3-fold, with no difference between transgenics and controls. However, HSL overexpression resulted in thicker aortic fatty lesions that were 2.5-times larger in transgenic mice. HSL expression in the aortic lesions was shown by immunocytochemistry. Atherosclerosis was more advanced in transgenic mice exhibiting raised lesions involving the aortic wall, along with lipid accumulation in coronary arteries occurring only in transgenics. Thus, increasing cholesteryl-ester hydrolysis, without concomitantly decreasing ACAT activity or increasing cholesterol efflux, is not sufficient to protect against atherosclerosis.—Escary, J-L., H. A. Choy, K. Reue, X-P. Wang, L. W. Castellani, C. K. Glass, A. J. Lusis, and M. C. Schotz. Paradoxical effect on atherosclerosis of hormone-sensitive lipase overexpression in macrophages. J. Lipid Res. 1999. 40: 397–404.http://www.sciencedirect.com/science/article/pii/S0022227520324433cholesteryl-ester hydrolysisacyl-CoA:cholesterol acyltransferasefoam cellsaortic lesionstransgenic mice |
| spellingShingle | Jean-Louis Escary Henry A. Choy Karen Reue Xu-Ping Wang Lawrence W. Castellani Christopher K. Glass Aldons J. Lusis Michael C. Schotz Paradoxical effect on atherosclerosis of hormone-sensitive lipase overexpression in macrophages Journal of Lipid Research cholesteryl-ester hydrolysis acyl-CoA:cholesterol acyltransferase foam cells aortic lesions transgenic mice |
| title | Paradoxical effect on atherosclerosis of hormone-sensitive lipase overexpression in macrophages |
| title_full | Paradoxical effect on atherosclerosis of hormone-sensitive lipase overexpression in macrophages |
| title_fullStr | Paradoxical effect on atherosclerosis of hormone-sensitive lipase overexpression in macrophages |
| title_full_unstemmed | Paradoxical effect on atherosclerosis of hormone-sensitive lipase overexpression in macrophages |
| title_short | Paradoxical effect on atherosclerosis of hormone-sensitive lipase overexpression in macrophages |
| title_sort | paradoxical effect on atherosclerosis of hormone sensitive lipase overexpression in macrophages |
| topic | cholesteryl-ester hydrolysis acyl-CoA:cholesterol acyltransferase foam cells aortic lesions transgenic mice |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520324433 |
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