Apolipoprotein B in the rough endoplasmic reticulum: Translation, translocation and the initiation of lipoprotein assembly

Apolipoprotein (apo) B and the microsomal triglyceride transfer protein are essential for the hepatic assembly and secretion of triglyceride-rich VLDL , To understand how apoB initiates the process of lipoprotein formation, in terest has focused on the biogenesis of its amino terminal globular domain (cr, domain). When only this domain is expressed in hepatoma cells, no lipo protein particle will form. However, proper folding of the ct, domain is es sential for the internal lipophilic regions of apoB to engage in cotranslat ional lipid recruitment. The essential function of this domain may be relat ed to its capacity to promote a specific physical interaction with the micr osomal triglyceride transfer protein, necessary for apoB's proper folding a nd lipidation, Alternatively, this domain may promote an autonomous lipid r ecruitment step that nucleates microsomal triglyceride transfer protein-dep endent lipid sequestration by apoB, Forms of apoB that fail to initiate par ticle assembly or forms associated with aberrant underlipidated particles a re targeted for intracellular turnover. Two sites of apoB degradation have been identified. In hepatocarcinoma-derived cells, misassembled apoB may un dergo progressive reverse translocation from the endoplasmic reticulum lume n to the cytosol, a process that is mechanistically coupled to polyubiquiti nation and proteasome-mediated degradation on the cytosolic side of the mem brane. Alternatively, studies in primary hepatocytes reveal that apoB may u ndergo sorting to a post-endoplasmic reticulum compartment for presecretory degradation. In either case, the balance between assembly and presecretory degradation of apoB may represent a control point for the production of he patic VLDL.