1. ¹Cardiovascular Disease Laboratory, Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan
2. ²Analytical Research Center for Experimental Sciences, Saga University, Saga, Japan
3. ³Department of Pharmacology, Dalian Medical University, Dalian, China
4. ⁴Laboratory of Chemistry, College of Liberal Arts and Sciences, Tokyo Medical and Dental University, Tokyo, Japan
5. ⁵Yamanouchi Pharmaceutical Company, Tsukuba Research Institute, Tsukuba, Japan
6. ⁶Saga University, Saga, Japan
7. ⁷Division of Metabolism and Endocrinology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan

Correspondence: Dr J Fan, Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan. E-mail: J-LFAN@md.tsukuba.ac.jp

Received 26 December 2003; Revised 18 February 2004; Accepted 19 February 2004; Published online 3 May 2004.

Abstract

Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyceride-rich lipoproteins. Previous studies using transgenic mice and rabbits have demonstrated that high level of LPL activity in adipose and skeletal muscle protects against diet-induced hypercholesterolemia and subsequently prevents aortic atherosclerosis. However, it is unknown, per se, whether increased LPL activity itself is antiatherogenic, or whether the antiatherogenic effect of LPL is dependent upon the LPL lipid-lowering effect. To address this issue, we fed LPL transgenic and littermate rabbits diets containing different amounts of cholesterol (0.3–0.6%) adjusted to maintain their plasma cholesterol concentrations at similarly high levels for 16 weeks. We analyzed their lipoprotein profiles and compared their susceptibility to atherosclerosis. The results showed that the overexpression of LPL in transgenic rabbits reduced remnant lipoproteins (-VLDL, d<1.006 g/ml) but concomitantly led to a significant increase of the large (d=1.02–1.04 g/ml) and small LDLs (d=1.04–1.06 g/ml) compared to the amounts in control rabbits. Furthermore, we found that with equally high hypercholesterolemia, transgenic rabbits developed 1.8-fold more extensive aortic atherosclerosis than control rabbits. To examine the hypothesis that altered lipoprotein profiles may be responsible for the enhanced atherosclerosis in transgenic rabbits, we studied the atherogenic properties of apoB-containing lipoproteins in vitro. These studies revealed that small-sized LDLs of transgenic rabbits were more susceptible to copper-induced oxidation and had higher affinity to biglycan than large remnant lipoproteins. We conclude, therefore, that LPL exerts a dual function in terms of its atherogenicity, namely antiatherogenicity, through enhancing receptor-mediated remnant lipoprotein catabolism and proatherogenicity via the generation of a large amount of small-sized LDLs. At an equal atherogenic-cholesterol level, small and dense LDLs are more atherogenic than large remnant lipoproteins.