Role of ApoE in Lipoprotein Metabolism and Type III HLP

Type III HLP is a genetic disorder of lipid metabolism characterized by the accumulation of remnant lipoproteins in the plasma and the development of premature atherosclerosis. Although receptor-binding-defective forms of apoE are the common denominator in all patients with type III HLP, there are still a number of apparent paradoxes concerning its pathogenesis. However, our studies in transgenic animal models have contributed significantly to resolving the mechanisms underlying the pathogenesis of this disorder (4–6). Drs. Yadong Huang and Zhong-Sheng Ji coordinate this component of the research program.

Type III HLP can be transmitted as either a recessive or a dominant trait. Recessive type III HLP is associated with homozygosity for apoE2(Cys112,Cys158), which is defective in binding to the low density lipoprotein (LDL) receptor. On the other hand, several rare variants of apoE are associated with dominant inheritance of type III HLP. Two major factors may determine recessive versus dominant inheritance of type III HLP. One is the VLDL preference of the apoE variants; the other is the binding affinity of the apoE variants to heparan sulfate proteoglycans (HSPG), which mediate the initial step of remnant clearance. To assess the importance of the VLDL preference of apoE variants in determining the mode of inheritance of type III HLP, we generated transgenic mice expressing apoE(Arg112,Cys158), a mutation that does not occur in nature and that combines two properties of apoE2(Cys112,Cys158) and apoE4(Arg112,Arg158): the LDL receptor–binding defect due to Cys158 and the VLDL preference due to Arg112.

As expected, the substitution of arginine for cysteine at position 112 significantly increased the amount of the unnatural apoE(Arg112,Cys158) in VLDL (23 ± 2%) and intermediate density lipoproteins (IDL) (20 ± 2%) compared with apoE2(Cys112,Cys158) (VLDL, 4 ± 1%; IDL, 4 ± 2%). Although low-level expression (<5 mg/dl) of the unnatural apoE(Arg112,Cys158) did not significantly alter plasma lipid levels, medium-level expression (5–10 mg/dl) in transgenic mice increased plasma levels of total cholesterol and triglycerides by 50% and 169%, respectively, compared with wild-type mice. Mice expressing high levels (>10 mg/dl) of the unnatural apoE(Arg112,Cys158) had threefold and sevenfold higher plasma levels of total cholesterol and triglycerides, respectively, than wild-type mice, whereas transgenic mice expressing similar levels of apoE2(Cys112,Cys158) developed hypocholesterolemia (49 ± 6 versus 93 ± 15 mg/dl). The hyperlipidemia in transgenic mice expressing the unnatural apoE(Arg112,Cys158) was caused by a marked accumulation in the plasma of VLDL- and IDL-sized lipoproteins as determined by fast-performance liquid chromatography (Figure 1). Both VLDL and IDL from the apoE(Arg112,Cys158)-expressing mice migrated at the b position on agarose gel electrophoresis, representing remnant lipoproteins (b-VLDL). These results suggest that residue 112 determines the lipoprotein preference of apoE2 and, in the context of Cys158, determines whether type III HLP is transmitted as a recessive or a dominant trait in transgenic mice (6).

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