Lipoproteins play a central role in the development of atherosclerotic cardiovascular disease in humans. The plasma concentrations of lipoproteins and their metabolic fates are modulated by apolipoproteins on the surface of these lipid-rich particles. The hypothesis has been raised that genetic variation in apolipoproteins is a major determinant of the interindividual variation in susceptibility to coronary artery disease (CAD). In humans, the structural gene locus for plasma apolipoprotein E (apo E) is polymorphic:1 " 6 three common alleles, designated e4, e3, and e2, code for three major apo E isoforms in plasma, respectively designated apo E4, apo E3, and apo E2. Apo E is a key protein in the modulation of the metabolism of the highly atherogenic apo B-containing lipoproteins. Therefore, apo E provides a good model to test the above hypothesis.The existence of a polymorphism for such an important apolipoprotein has been a source of major interest in recent years and has raised many questions for clinicians, epidemiologists, geneticists, and biochemists. The similarities of the relative frequencies of the three common alleles among populations representing very different ethnic, cultural, and geographic settings; their different effects on •lipoprotein metabolism; and their association with certain lipid transport disorders have stimulated research aimed at a better understanding of their role in health and disease. A wealth of information 7 " 18 has accrued from studies on apolipoprotein E structure, metabolism, and function. These have considerably advanced our knowledge of the role of apo E in normal and abnormal lipoprotein metabolism, the complex interactions leading to hyperfipidemia and atherosclerosis, and the pathogenesis of type III hyperiipoproteinemia. Of major interest is the observation that the protein products of the e4 and E2 alleles have separate, and in some circumstances opposite, influences on plasma lipo- protein concentrations, a finding which leads to the hypothesis that the apo E polymorphism ranks among the major factors involved in determining interindividual differences in the initiation and progression of atherosclerosis. The evidence associating the apo E polymorphism with altered lipid and lipoprotein levels and atherosclerosis will be reviewed here. First, the apo E gene and gene product will be considered with a brief overview of molecular biology, protein chemistry, and methods for phenotyping. Second, the impact of variation at the apo E locus on plasma lipids and lipoproteins in health and disease will be discussed. Third, the metabolic interactions accounting for the various effects of the different alleles on lipids and lipoproteins will be considered to provide a unifying interpretation as to how apo E modulates the metabolism of apo B-containing lipoproteins and their remnants. Last, direct evidence associating the apo E polymorphism and atherosclerosis will be reviewed and discussed. This review is not intended to be all-inclusive, and the reader is referred to recent r...

Abetalipoproteinemia is a human genetic disease that is characterized by a defect in the assembly or secretion of plasma very low density lipoproteins and chylomicrons. The microsomal triglyceride transfer protein (MTP), which is located in the lumen of microsomes isolated from the liver and intestine, has been proposed to function in lipoprotein assembly. MTP activity and the 88-kilodalton component of MTP were present in intestinal biopsy samples from eight control individuals but were absent in four abetalipoproteinemic subjects. This finding suggests that a defect in MTP is the basis for abetalipoproteinemia and that MTP is indeed required for lipoprotein assembly.

Inhibition of the microsomal triglyceride transfer protein by BMS-201038 resulted in the reduction of LDL cholesterol levels in patients with homozygous familial hypercholesterolemia, owing to reduced production of apolipoprotein B. However, the therapy was associated with elevated liver aminotransferase levels and hepatic fat accumulation.

The microsomal triglyceride transfer protein (MTP), which catalyses the transport of triglyceride, cholesteryl ester and phospholipid between phospholipid surfaces, is a heterodimer composed of the multifunctional protein, protein disulphide isomerase, and a unique large subunit with an apparent M(r) of 88K (refs 1-3). It is isolated as a soluble protein from the lumen of the microsomal fraction of liver and intestine. The large subunit of MTP was not detectable in four unrelated subjects with abetalipoproteinaemia, a rare autosomal recessive disease characterized by a defect in the assembly or secretion of plasma lipoproteins that contain apolipoprotein B (ref. 6). We report here the isolation and sequencing of complementary DNA encoding the large subunit of MTP. A comparison of this sequence to corresponding genomic sequences from two abetalipoproteinaemic subjects revealed a homozygous frameshift mutation in one subject and a homozygous nonsense mutation in the other. The results indicate that a defect in the gene for the large subunit of MTP is the proximal cause of abetalipoproteinaemia in these two subjects, and that MTP is required for the secretion of plasma lipoproteins that contain apolipoprotein B.

Apolipoprotein E (apoE) is important in modulating the catabolism of remnants of triglyceride-rich lipoprotein particles. It is a polymorphic protein with the three common alleles coding for apoE2, apoE3, and apoE4. ApoE3 is considered the normal isoform, while apoE4 is associated both with hypercholesterolemia and type V hyperlipoproteinemia. We quantitated the kinetics of metabolism of apoE4 in 19 normolipidemic apoE3 homozygotes and 1 normolipidemic apoE4 homozygote, and compared this with the metabolism of apoE3 in 12 normolipidemic apoE3 homozygotes. In the apoE3 homozygous subjects, apoE4 was catabolized twice as fast as apoE3, with a mean plasma residence time of 037±0.01 d (±SEM) and 0.73±0.05 (P < 0.001), respectively. When plasma was fractionated into the lipoprotein subclasses, the greatest amount of labeled apoE4 was present on very low density lipoproteins, while the largest fraction of labeled apoE3 was associated with high density lipoproteins.The plasma apoE concentration was decreased in an apoE4 homozygote compared with the apoE3 homozygotes (3.11 mg/ dl vs. 4.83±0.35 mg/dl). The reduced apoE4 concentration was entirely due to a decreased apoE4 residence time in the apoE4 homozygote (0.36 d vs. 0.73±0.05 d for apoE3 in apoE3 homozygotes).These results indicate that apoE4 is kinetically different than apoE3, and suggest that the presence of apoE4 in hypercholesterolemic and type V hyperlipoproteinemic individuals may play an important pathophysiological role in the development of these dyslipoproteinemias.