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 residues. The small intestine of all mammals secretes apoB48, which arises following C-to-U deamination of a single cytidine base in the nuclear apoB transcript, 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 protein factors that have yet to be cloned. ApoB RNA editing also exhibits stringent cis-acting requirements that include both structural and sequence-specific elements-specifically efficiency elements that flank the minimal cassette, an AU-rich RNA context, and an 11-nucleotide mooring sequence-located in proximity to a suitably positioned (usually upstream) cytidine. C-to-U RNA editing may become unconstrained under circumstances where apobec-1 is overexpressed, in which case multiple cytidines in apoB RNA, as well as in other transcripts, undergo C-to-U editing. ApoB RNA editing is eliminated following targeting of apobec-1, establishing that there is no genetic redundancy in this function. Under physiological circumstances, apoB RNA editing exhibits developmental, hormonal, and nutritional regulation, in some cases related to transcriptional regulation of apobec-1 mRNA. ApoB and the microsomal triglyceride transfer protein (MTP) are essential for the assembly and secretion of apoB-containing lipoproteins. MTP functions by transferring lipid 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-density lipoproteins or chylomicrons. In cultured hepatic cells, lipid availability dictates the rate of apoB production. Unlipidated or underlipidated forms of apoB are subjected to presecretory degradation, a process mediated by retrograde transport from the lumen of the endoplasmic reticulum to the cytosol, coupled with multiubquitination and proteasomal degradation. Although control of lipid secretion in vivo is primarily achieved at the level of lipoprotein particle size, regulation of apoB production by presecretory degradation may be relevant in some dyslipidemic states.
Davidson
N O
NO
Departments of Medicine and Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, Missouri 63110, USA. nod@im.wustl.edu
Shelness
G S
GS
D000818:Animals; D001055:Apolipoproteins B / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D002914:Chylomicrons / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids / Q000235:genetics; D008099:Liver / Q000378:metabolism; D017393:RNA Editing; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism
D001055:Apolipoproteins B; D002914:Chylomicrons; D008055:Lipids; D012333:RNA, Messenger