Plasma and vessel wall lipoprotein lipase have different roles in atherosclerosis

Susanne M Clee,Nagat Bissada,Fudan Miao,Li Miao,A David Marais,Howard E Henderson,Pieternel Steures,Janet Mcmanus,Bruce Mcmanus,Renee C Leboeuf,John J.P Kastelein,Michael R Hayden

doi:10.1016/s0022-2275(20)32399-3

Abstract

Lipoprotein lipase (LPL) is a key enzyme in lipoprotein metabolism, and has been hypothesized to exert either pro- or anti-atherogenic effects, depending on its localization. Decreased plasma LPL activity is associated with the high triglyceride (TG)–low HDL phenotype that is often observed in patients with premature vascular disease. In contrast, in the vessel wall, decreased LPL may be associated with less lipoprotein retention due to many potential mechanisms and, therefore, decreased foam cell formation. To directly assess this hypothesis, we have distinguished between the effects of variations in plasma and/or vessel wall LPL on atherosclerosis susceptibility in apoE-deficient mice. Reduced LPL in both plasma and vessel wall (LPL+/− E−/−) was associated with increased TG and increased total cholesterol (TC) compared with LPL+/+E−/− sibs. However despite their dyslipidemia, LPL+/−E−/− mice had significantly reduced lesion areas compared to the LPL+/+E−/− mice. Thus, decreased vessel wall LPL was associated with decreased lesion formation even in the presence of reduced plasma LPL activity. In contrast, transgenic mice with increased plasma LPL but with no increase in LPL expression in macrophages, and thus the vessel wall, had decreased TG and TC and significantly decreased lesion areas compared with LPL+/+E−/− mice. This demonstrates that increased plasma LPL activity alone, in the absence of an increase in vessel wall LPL, is associated with reduced susceptibility to atherosclerosis. Taken together, these results provide in vivo evidence that the contribution of LPL to atherogenesis is significantly influenced by the balance between vessel wall protein (pro-atherogenic) and plasma activity (anti-atherogenic).—Clee, S. M., N. Bissada, F. Miao, L. Miao, A. D. Marais, H. E. Henderson, P. Steures, J. McManus, B. McManus, R. C. LeBoeuf, J. J. P. Kastelein, and M. R. Hayden. Plasma and vessel wall lipoprotein lipase have different roles in atherosclerosis. J. Lipid Res. 2000. 41: 521–531.

Highlights

Lipoprotein lipase (LPL) is a key enzyme in lipoprotein metabolism, and has been hypothesized to exert either pro- or anti-atherogenic effects, depending on its localization
In an effort to validate these findings in another mouse model, we explored the relationship between variations in LPL and atherogenesis by examining diet-induced atherosclerosis in a C57BL/6 (BL/6) mouse model with similar alterations in LPL
In two different models of atherosclerosis, we have provided in vivo evidence for the differing influence of LPL in the development of atherosclerosis depending on its site of expression

Summary

Introduction

Lipoprotein lipase (LPL) is a key enzyme in lipoprotein metabolism, and has been hypothesized to exert either pro- or anti-atherogenic effects, depending on its localization. In the vessel wall, decreased LPL may be associated with less lipoprotein retention due to many potential mechanisms and, decreased foam cell formation. Transgenic mice with increased plasma LPL but with no increase in LPL expression in macrophages, and the vessel wall, had decreased TG and TC and significantly decreased lesion areas compared with LPL؉/؉E؊/؊ mice. This demonstrates that increased plasma LPL activity alone, in the absence of an increase in vessel wall LPL, is associated with reduced susceptibility to atherosclerosis.

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Results

Conclusion