**4. Species differences in phenotypes between genetically modified animals**

Table 2 shows species differences in phenotypes of lipoprotein metabolism between genetically modified animals when the same genes were modified. Overexpression of apoB-100 increased HDL-cholesterol but had no effect on non-HDL-cholesterol in mice fed a chow diet (Farese, 1996) but increased in cholesterol levels in plasma and LDL in rabbits (Fan, 1995). Overexpression of apoE decreased levels of apoB-containing lipoproteins in mice (Shimano, 1992) but increased cholesterol levels in plasma and LDL in rabbits (Fan, 1998). In addition, overexpression of PLTP increased HDL-cholesterol and apoA-I levels but did not affect LDL-cholesterol in mice (Jiang, 1996), while it increased LDL-cholesterol and did not affect HDL in rabbits (Masson, 2011). These differences may be due to high CETP activity in rabbits and no CETP activity in mice. Lipoprotein(a) is detected in humans and monkeys, and is an atherogenic lipoprotein. In mice overexpressing human apo(a) (Chiesa, 1992), apo(a) did not bind to mouse LDL particles, while in rabbits, human apo(a) can bound to rabbit LDL particles and formed Lp(a) (Rouy, 1998; Fan, 1999). Finally, LDLR-KO increased cholesterol levels mildly in plasma and LDL in mice (Ishibashi, 1993) and rats (Asahina, 2012), while spontaneous LDLR-deficient rabbits (WHHL or WHHLMI rabbits) show severe hypercholesterolemia due to the accumulation of LDL in plasma even on a normal diet (Goldstein, 1993; Shiomi, 2003; 2009). In humans, LDLR-deficiency produces severe hypercholesterolemia due to the accumulation of LDL in plasma. These differences in effects of LDLR between humans / rabbits and mice / rats may be due to the expression of apobec-1 in the liver and CETP activity in the plasma. Therefore, one has to consider species differences when using animal models. LDLR-KO mice on a high-fat diet showed dramatic hypercholesterolemia (Ishibashi, 1994), and the plasma cholesterol level is comparable with or higher than that of apoE-KO mice. In contrast, the degree of atherosclerosis is greater in apoE-KO mice than LDLR-KO mice. In addition, LDLR-KO mice on a chow diet did not show massive atherosclerotic lesions at the age of 12 months (Ishibashi, 1994), while apoE-KO mice on a chow diet for the same period showed massive atherosclerotic lesions (Zhang, 1992 and Reddick, 1994). These differences in plasma lipid profiles and atherosclerosis are not fully understood but are likely to be attributable to the quality or subtype of the circulating lipoproteins.

546 Lipoproteins – Role in Health and Diseases

*3.5.4. HDL receptors* 

**animals** 

in a high-cholesterol deiet feeding (Masson, 2011). These differences in the function of PLTP between mice and rabbits may be due to fundamental differences in lipoprotein metabolism, such as CETP activity in the plasma and apobec-1 expression in the liver. Therefore, one has

HDL particles are incorporated by SR-BI, a HDL receptor, expressed in liver. In humans and rabbits, cholesterol is transferred from peripheral macrophages to liver through two pathways, via CETP-LDLR and SR-BI, while in mice and rats, cholesterol is transported to liver via SR-BI expressed in liver. Overexpression of SR-BI in mice induces a decrease in plasma lipids and an increase in the fractional catabolic rate for HDL (Wang, 1998). In contrast, SR-BI-KO mice show increases in plasma cholesterol levels, HDL particle size, and levels of apoE and apoA-I in HDL particles (Rigotti, 1997). These results demonstrate the function of SR-BI in reverse cholesterol transport. However, these changes in plasma lipid

levels reflect HDL lipid levels, because mice do not have CETP activity in the plasma.

**4. Species differences in phenotypes between genetically modified** 

Table 2 shows species differences in phenotypes of lipoprotein metabolism between genetically modified animals when the same genes were modified. Overexpression of apoB-100 increased HDL-cholesterol but had no effect on non-HDL-cholesterol in mice fed a chow diet (Farese, 1996) but increased in cholesterol levels in plasma and LDL in rabbits (Fan, 1995). Overexpression of apoE decreased levels of apoB-containing lipoproteins in mice (Shimano, 1992) but increased cholesterol levels in plasma and LDL in rabbits (Fan, 1998). In addition, overexpression of PLTP increased HDL-cholesterol and apoA-I levels but did not affect LDL-cholesterol in mice (Jiang, 1996), while it increased LDL-cholesterol and did not affect HDL in rabbits (Masson, 2011). These differences may be due to high CETP activity in rabbits and no CETP activity in mice. Lipoprotein(a) is detected in humans and monkeys, and is an atherogenic lipoprotein. In mice overexpressing human apo(a) (Chiesa, 1992), apo(a) did not bind to mouse LDL particles, while in rabbits, human apo(a) can bound to rabbit LDL particles and formed Lp(a) (Rouy, 1998; Fan, 1999). Finally, LDLR-KO increased cholesterol levels mildly in plasma and LDL in mice (Ishibashi, 1993) and rats (Asahina, 2012), while spontaneous LDLR-deficient rabbits (WHHL or WHHLMI rabbits) show severe hypercholesterolemia due to the accumulation of LDL in plasma even on a normal diet (Goldstein, 1993; Shiomi, 2003; 2009). In humans, LDLR-deficiency produces severe hypercholesterolemia due to the accumulation of LDL in plasma. These differences in effects of LDLR between humans / rabbits and mice / rats may be due to the expression of apobec-1 in the liver and CETP activity in the plasma. Therefore, one has to consider species differences when using animal models. LDLR-KO mice on a high-fat diet showed dramatic hypercholesterolemia (Ishibashi, 1994), and the plasma cholesterol level is comparable with or higher than that of apoE-KO mice. In contrast, the degree of atherosclerosis is greater in

to be deliberate in interpreting results from gene modification studies.


**Table 2.** Species differences in phenotype on overexpression of the same genes.
