**1. Introduction**

532 Lipoproteins – Role in Health and Diseases

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Coronary artery disease (CAD) is a leading cause of death in the world and one of the major risk factors for CAD is dyslipidemia. In understanding dyslipidemia and developing therapeutics, animal models, especially genetically modified animals, have played important roles and contributed greatly to progress in this field. Before the development of genetically modified animals, the Watanabe heritable hyperlipidemic (WHHL) rabbit, the first animal model for familial hypercholesterolemia, developed by Yoshio Watanabe in 1980 (Watanabe, 1980), helped to verify a low-density lipoprotein (LDL) receptor-pathway in vivo and to clarify lipoprotein metabolism in humans (Goldstein, 1983), in addition to the process by which atherosclerosis develops (Shiomi, 2009). Furthermore, WHHL rabbits have contributed to the development of hypocholesterolemic agents, statins, (Watanabe, 1981; Tsujita, 1986) and to clarifying anti-atherosclerotic effects (Watanabe, 1988; Shiomi, 1995; 2009). In the present, WHHL rabbits were improved by selective breeding to produce the WHHLMI strain, which suffers from severe and vulnerable coronary atheromatous plaques and myocardial infarction due to coronary occlusion with progression of atherosclerotic plaques (Shiomi, 2003). However, WHHL or WHHLMI rabbits were not suitable for studying the role of genes in lipid metabolism, because it is difficult to apply genetic modification techniques to rabbits.

The first transgenic mice were developed in 1982 (Gordon, 1982) and the first knockout mice in 1984 (Bradley, 1984). Genetically modified mice are commonly used to study lipoprotein metabolism and atherosclerosis. The first transgenic mice for lipoprotein metabolism were LDLR-overexpressing mice, developed in 1988 (Hofmann, 1988), and the

© 2012 Shiomi et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

first knockout (KO) mice for lipoprotein metabolism were apolipoprotein (apo) E-KO mice, developed in 1992 (Zhang, 1992). Thereafter, numerous genetically modified mouse models were produced and these mice have contributed to a better understanding of lipoprotein metabolism. However, we should recognize that the lipoprotein metabolism of genetically modified mice is not entirely the same as that of humans, despite hyperlipidemia or hypercholesterolemia. In addition, recent studies have demonstrated different phenotypes manifested in mice and rabbits after the same gene transfer (Fan, 2003). The first transgenic rabbit was developed in 1985 (Hammer, 1985) and the first transgenic rabbit for lipoprotein metabolism, the hepatic lipase-overexpressing rabbit, was developed in 1994 (Fan, 1994). The differences in phenotype following gene transfer between mice and rabbits may be due to species differences in lipoprotein metabolism. When using animal models in experimental research, one has to be careful interpreting the results. Since other chapters explain in detail the functions of enzymes, apolipoproteins, and receptors relating to lipoprotein metabolism, this chapter concentrates on introducing various genetically modified animals and species differences in phenotype expression after gene modification for researchers wishing to study lipoprotein metabolism.
