**5. Genetically modified animal models for human dyslipidemia**

Table 3 summarizes plasma lipid profiles of genetically modified animal models for human dyslipidemia. Plasma lipid and/or lipoprotein profiles of genetically modified mice resemble those for human diseases involving apoC-II deficiency, LPL deficiency, and CETP deficiency. However, plasma lipid levels and lipoprotein profiles of genetically deficient mice are markedly different from those of humans with a deficiency of ABCA1, apoE or LDLR. In ABCA1-KO mice, cholesterol levels markedly decreased in not only HDL but whole plasma, while patients with Tangier disease, who do not have ABCA1 and show very low levels of HDL-cholesterol, exhibit a mild decrease in plasma cholesterol levels. This difference between ABCA1-KO mice and patients with Tangier disease may be due to CETP activity in plasma. ApoE-KO mice fed normal chow show hypercholesterolemia and the increased lipoprotein fraction is VLDL, which contains apoB-48, although plasma triglyceride levels are almost normal. In addition, HDL-cholesterol levels are markedly low. However, patients with apoE deficiency show type III hyperlipidemia by the WHO classification. The increased lipoprotein is VLDL and IDL, and both cholesterol and triglyceride levels are increased. HDL cholesterol is almost normal (Mabuchi, 1989). These differences in lipoprotein metabolism between mice and patients may be due to the expression of apobec-1 in mouse liver and the triglyceride content of the VLDL fraction. Considering these observations, the hypercholesterolemia in apoE-KO mice may not reflect human hypercholesterolemia. In LDLR deficiency, although humans and rabbit models show marked hypercholesterolemia due to the accumulation of LDL in plasma despite a normal diet (Watanabe, 1980; Shiomi, 2009), the accumulation of LDL in plasma in homozygous LDLR-KO mice is mild (Ishibashi, 1993; 1994). These differences in plasma lipid levels and lipoprotein profiles between LDLR-KO mice and familial hypercholesterolemia or WHHL rabbits are due to the rapid clearance of apoB-48-containing VLDL, IDL, and LDL through apoER in mouse liver. Recently, LDLR-KO rats were developed (Asahina, 2012) . These animals have a similar lipoprotein profile to LDLR-KO mice. Studies demonstrate that both the expression of apobec-1 in liver and a deficiency of CETP in plasma greatly affect lipoprotein metabolism and plasma lipid levels in mice and rats. To solve these problems with LDLR-KO mice and apoE-KO mice, cross breeding with apobec-1-KO/CETP-expressing animals may be required in studies of lipoprotein metabolism. In the development of statins, potent anti-hyperlipidemic agents used by more than 40 million patients world-wide, no cholesterol-lowering effect was observed in mice and rats, although strong cholesterol-lowering effects were found in rabbits, dogs, monkeys and chickens (Tsujita, 1986). In addition, simvastatin, a statin, did not decrease serum cholesterol levels in LDLR-KO mice and CETP(+/-)LDLR(-/-)mice, and increased serum cholesterol levels in apoE-KO mice at a dose of 30 mg/kg/day (Yin, 2012), although an extremely high dose of statins (0.168% in diet, 200-300 mg/kg/day) decreased serum cholesterol levels in LDLR-KO mice (Krause, 1998). In contrast, WHHL rabbits, an animal model of familial hypercholesterolemia, have played important roles in studies of the hypocholesterolemic effects and anti-atherosclerotic effects of statins (Shiomi, 1995; 2009). The cholesterol-lowering effect of statins is mainly mediated by an increase in LDLR in liver. Therefore, the effect is weak when the contribution of LDLR to the regulation of plasma cholesterol levels is small, as in mice and rats. These studies suggest the need to select animal models based on study purposes.


**Table 3.** Plasma lipid profiles of genetically modified animal models for human dyslipidemia

#### **6. Conclusion**

548 Lipoproteins – Role in Health and Diseases

models based on study purposes.

apoE-deficiency

LPL deficiency

due to the accumulation of LDL in plasma despite a normal diet (Watanabe, 1980; Shiomi, 2009), the accumulation of LDL in plasma in homozygous LDLR-KO mice is mild (Ishibashi, 1993; 1994). These differences in plasma lipid levels and lipoprotein profiles between LDLR-KO mice and familial hypercholesterolemia or WHHL rabbits are due to the rapid clearance of apoB-48-containing VLDL, IDL, and LDL through apoER in mouse liver. Recently, LDLR-KO rats were developed (Asahina, 2012) . These animals have a similar lipoprotein profile to LDLR-KO mice. Studies demonstrate that both the expression of apobec-1 in liver and a deficiency of CETP in plasma greatly affect lipoprotein metabolism and plasma lipid levels in mice and rats. To solve these problems with LDLR-KO mice and apoE-KO mice, cross breeding with apobec-1-KO/CETP-expressing animals may be required in studies of lipoprotein metabolism. In the development of statins, potent anti-hyperlipidemic agents used by more than 40 million patients world-wide, no cholesterol-lowering effect was observed in mice and rats, although strong cholesterol-lowering effects were found in rabbits, dogs, monkeys and chickens (Tsujita, 1986). In addition, simvastatin, a statin, did not decrease serum cholesterol levels in LDLR-KO mice and CETP(+/-)LDLR(-/-)mice, and increased serum cholesterol levels in apoE-KO mice at a dose of 30 mg/kg/day (Yin, 2012), although an extremely high dose of statins (0.168% in diet, 200-300 mg/kg/day) decreased serum cholesterol levels in LDLR-KO mice (Krause, 1998). In contrast, WHHL rabbits, an animal model of familial hypercholesterolemia, have played important roles in studies of the hypocholesterolemic effects and anti-atherosclerotic effects of statins (Shiomi, 1995; 2009). The cholesterol-lowering effect of statins is mainly mediated by an increase in LDLR in liver. Therefore, the effect is weak when the contribution of LDLR to the regulation of plasma cholesterol levels is small, as in mice and rats. These studies suggest the need to select animal

Gene modification Mice and/or rats Human

Tangier disease, Marked decrease in HDL cholesterol but mild decrease in plasma cholesterol

Combined hyperlipidemia Increase in IDL and no changes in HDL

> Hypercholesterolemia Marked increase in LDL

Hypertriglyceridemia

mice) High HDL cholesterol

levels in both plasma and HDL

Hypercholesterolemia Increase in VLDL and decrease in HDL

Mild increase in LDL

Hypertriglyceridemia Lethal right after birth in homozygotes

**Table 3.** Plasma lipid profiles of genetically modified animal models for human dyslipidemia

apoC-II deficiency Hypertriglyceridemia Hypertriglyceridemia

ABCA1 deficiency Marked decrease in cholesterol

LDLR-deficiency Mild increase in plasma cholesterol

CETP deficiency High HDL cholesterol (wild-type

In this chapter, the authors summarized achievements of studies using genetically modified animal models in lipoprotein research. The cross-breeding of genetically modified animals, such as double KO mice, triple KO mice, and others, has contributed to studies of lipoprotein metabolism. Studies using genetically modified mice have elucidated the mechanisms of cholesterol absorption in the intestine, lipolysis of apoB-containing lipoproteins, lipoprotein receptor function, and cholesterol efflux from macrophages to HDL. Although genetically modified animals are useful to elucidate the function of genes related to lipoprotein metabolism, we have to carefully select animal species to know the effect of these genes on lipid levels of whole plasma and lipoprotein profiles in humans. In addition, genetically modified mice have limitations in studies about the development of hypocholesterolemic agents, because of the expression of apobec-1 in liver and a deficiency of CETP activity in plasma. Consequently, these fundamental differences in lipoprotein metabolism between mice and humans affect the interpretation of results of gene modification about lipoprotein metabolism in mice. To solve these problems, genetically modified mice should be produced using CETP-transgenic/apobec-1-KO mice or animals having a background of no expression of apobec-1 in the liver and expression of CETP in plasma. We have to be careful in the interpretation of results obtained using genetically modified animals, and to select animal models in response to study purposes to extrapolate the results to humans. Recently, techniques of X-linked severe combined immunodeficiency (X-SCID) using zinc-finger nucleases, transcriptional activator-like effector nucleases (TALEN), and mutation using an N-ethyl-N-nitrosourea mutagenesis have become available for knockout gene expression. These techniques will be able to produce KO-animals other than mice. These animals will contribute further to studies of lipoprotein metabolism and lipid disorders in humans.

### **Author details**

Masashi Shiomi, Tomonari Koike and Tatsuro Ishida *Kobe University Graduate School of Medicine, Japan* 

### **Acknowledgement**

This work was supported in part by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports and Technology, Japan (23300157).

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**Role of Lipoproteins in Neurodegenerative Diseases** 

560 Lipoproteins – Role in Health and Diseases

*Invest*, Vol.96, No. 6, pp.2932-2946

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**Chapter 23** 
