Apolipoprotein B mRNA editing

Apolipoprotein Β (apo Β) is a large hydrophobic protein synthesized in the liver and small intestine of mammals. Apo Β serves an essential although incompletely understood role in the assembly and secretion of triglyceride-rich lipoproteins (chylomicrons and very low density lipoproteins) and also functions in the catabolic clearance of low density lipoprotein (LDL), the major transport vehicle of plasma cholesterol in humans. Mammalian apo Β is the product of a single gene which maps to the p23-p24 region of chromosome 2^1,2(for detailed reviews see References 3 and 4). Apo Β mRNA is expressed and processed in a tissue-specific fashion, the molecular and cellular basis for which will be the focus of this chapter. As currently viewed, one form of apo Β is synthesized in the human liver as a protein of 4536 amino acids with a relative molecular mass of 512,000. This form of the protein is referred to on a centile scale as apo Β100,^5-9 By contrast, the intestinal form of the protein contains 2152 amino acids, is colinear with the amino terminal half of apo B100, and is referred to as apo B48.^10,11 Several important structural domains have been identified for apo Β based upon cDNA sequence and monoclonal epitope mapping. The most important of these are the LDL receptor binding domain and the attachment site of apolipoprotein (a) which both reside in the carboxyl terminal half of the protein.^12-14 The biological relevance of apo B48 may thus relate to the absence of the above domains which are present only in the full length protein. Apo B48 is found in the systemic circulation in association with intestinally derived lipoprotein particles, namely chylomicrons and chylomicron remnants. These particles are cleared from the plasma compartment via a (principally hepatic) receptor which has been partially characterized and is referred to as the LDL receptor-related protein or LRP.^{15, 16} This receptor recognizes apolipoprotein E as its major ligand.¹⁷ Thus, lipoprotein particles containing apo B48 have a distinct catabolic fate from those with apo Β100 which are cleared principally via the LDL receptor. The implications for this observation in terms of atherosclerosis susceptibility remain to be tested experimentally, but it suggests several models whereby such characteristics of an intestinal particle may have evolved to facilitate their function as an efficient delivery system for dietary triglyceride. By contrast, the finer regulation of plasma cholesterol homeostasis may be achieved through hepatic very low density lipoprotein (VLDL) secretion and ultimately LDL uptake.