Apolipoprotein B: mRNA editing, lipoprotein assembly, and presecretory degradation

Apolipoprotein (apo)B circulates in two distinct forms, apoB100 and apoB48. Human liver secretes apoB100, the product of a large mRNA encoding 4536 re sidues. The small intestine of all mammals secretes apoB48, which arises fo llowing C-to-U deamination of a single cytidine base in the nuclear apoB tr anscript, introducing a translational stop codon. This process, referred to as apoB RNA editing, operates through a multicomponent enzyme complex that contains a single catalytic subunit, apobec-1, in addition to other protei n factors that have yet to be cloned. ApoB RNA editing also exhibits string ent cis-acting requirements that include both structural and sequence-speci fic elements-specifically efficiency elements that flank the minimal casset te, an AU-rich RNA context, and an Il-nucleotide mooring sequence-located i n proximity to a suitably positioned (usually upstream) cytidine. C-to-U RN A editing may become unconstrained under circumstances where apobec-1 is ov erexpressed, in which case multiple cytidines in apoB RNA, as well as in ot her transcripts, undergo C-to-U editing. ApoB RNA editing is eliminated fol lowing targeting of apobec-1, establishing that there is no genetic redunda ncy in this function. Under physiological circumstances, apoB RNA editing e xhibits developmental, hormonal, and nutritional regulation, in some cases related to transcriptional regulation of apobec-1 mRNA. ApoB and the micros omal triglyceride transfer protein (MTP) are essential for the assembly and secretion of apoB-containing lipoproteins. MTP functions by transferring l ipid to apoB during its translation and by transporting triglycerides into the endoplasmic reticulum to form apoB-free lipid droplets. These droplets fuse with nascent apoB-containing particles to form mature, very low-densit y lipoproteins or chylomicrons. In cultured hepatic cells, lipid availabili ty dictates the rate of apoB production. Unlipidated or underlipidated form s of apoB are subjected to presecretory degradation, a process mediated by retrograde transport from the lumen of the endoplasmic reticulum to the cyt osol, coupled with multiubquitination and proteasomal degradation. Although control of lipid secretion in vivo is primarily achieved at the level of L ipoprotein particle size, regulation of apoB production by presecretory deg radation may be relevant in some dyslipidemic states.