Superior role of apolipoprotein B48 over apolipoprotein B100 in chylomicron assembly and fat absorption: an investigation of apobec-1 knock-out and wild-type mice

Abstract

Editing of apolipoprotein (apo)-B100 mRNA to yield apo-B48 is a specific and developmentally regulated step in enterocytes of mammals. However, the functional significance of this step is not known. Since mice containing only apo-B100have not been documented to exhibit any difference in intestinal fat absorption from wild-type mice, the evolutionary advantage of apoB mRNA editing has been questioned. In the present study, we have compared fat absorption and chylomicron assembly in apobec-1 knock-out (KO) or wild-type (WT) mice subjected to different dietary manipulations: low-fat chow, a fat-enriched ‘Western’ diet and overnight fasting. Experiments in vivo and in vitro revealed differences in the ability of KO and WT enterocytes to assemble and secrete chylomicrons under different dietary conditions. After overnight fasting, chylomicron secretion is reduced considerably in KO compared with WT enterocytes. This is not due to reduced synthesis of apo-B or triacylglycerol (TAG), but appears to be a result of impaired assembly of chylomicrons, so that triacylglycerol accumulates in the enterocytes. After feeding with fat, secretion of chylomicrons enriched in pre-existing TAG is stimulated in KO compared with WT mice. In the present study, we have documented for the first time that apo-B100 is considerably less efficient than apo-B48 in exerting its role in the early stage of chylomicron assembly, which is rate-limiting under conditions of low dietary fat. However, this impairment is overcome by increased TAG stores that stimulate later stages in assembly, which are rate-limiting in the fat-fed state. apo-B mRNA editing may result in more efficient fat absorption, specifically under conditions of food shortage or low-fat content, and thus provide an evolutionary advantage.