For the past 5 years, investigators from many different laboratories have contributed to a greatly increased understanding of two very important lipid-carrying proteins in plasma--apo B-100 and apo B-48. Apo B-100, an extremely large protein composed of 4,536 amino acids, is synthesized by the liver and is crucial for the assembly of triglyceride-rich VLDL particles. Apo B-100 is virtually the only protein of LDL, a cholesteryl ester-enriched class of lipoproteins that are metabolic products of VLDL. The apo B-100 of LDL serves as a ligand for the LDL receptor-mediated uptake of LDL particles by the liver and extrahepatic tissues. The LDL receptor-binding region of apo B-100 is located in the carboxyterminal portion of the molecule, whereas its lipid-binding regions appear to be broadly dispersed throughout its length. Apo B-48 contains the amino-terminal 2,152 amino acids of apo B-100 and is produced by the intestine as a result of editing of a single nucleotide of the apo B mRNA, which changes the codon...

Recent progress in understanding apolipoprotein B.

In contrast to water-soluble fuels such as glucose or ketone bodies, the use of lipids as an energy source for tissues has required the development of complex structures for their transport through the aqueous plasma. In the case of endogenously synthesized triacylglycerol this is achieved by the assembly and secretion of hepatic VLDL which provides the necessary stability in an aqueous medium. An essential component of this assembly process is apo B. Dietary changes which require an increase in hepatic VLDL secretion appear to be accompanied by increases in the availability of functional apo B. Interesting questions relate to: (a) the intracellular site(s) of triacylglycerol association with apo B, and (b) the mechanism(s) by which the availability of functional apo B at this site responds to metabolic and hormonal signals which reflect dietary status and, thus, the need to secrete triacylglycerol. As regards the latter, although in some cases changes in apo B synthesis occur in response to VLDL secretion hepatic apo B mRNA levels appear to be quite stable in vitro. Intracellular switching of apo B between the secretory and degradative pathways may be important in controlling VLDL assembly and post-translational modifications of the apoprotein may also play a role by influencing its ability to bind to triacylglycerol. Transport is not the only problem associated with the utilization of a concentrated energy source such as triacylglycerol and the complex problems of waste product disposal and recycling have to be dealt with. In the case of triacylglycerol, potentially toxic waste products include atherogenic remnants and LDL. The overall problem, then, in the long-term, involves the development of a ‘safe’ means of utilizing triacylglycerol and this requirement accounts for much of the complexity of plasma lipoprotein metabolism. In this area, the rat could teach the human a few tricks. One of these appears to be the utilization of hepatic apo B48 rather than apo B100 for VLDL assembly in response to increases in the extrahepatic utilization of hepatically synthesized triacylglycerol. Under these conditions, the remnants of hepatic triacylglycerol utilization by peripheral tissues are cleared from the plasma much more readily via a process which seems to involve the cycling of more triacylglycerol back to the liver than that which occurs in humans. The means by which this is achieved, though, are obscure and may involve a chylomicron remnant receptor, the nature of which, itself, remains controversial.(ABSTRACT TRUNCATED AT 400 WORDS)

/pdf/assembly-and-secretion-of-hepatic-very-low-density-w1cngvpkwx.pdf

Assembly and secretion of hepatic very-low-density lipoprotein.

Apolipoprotein B mRNA editing in 12 different mammalian species: hepatic expression is reflected in low concentrations of apoB-containing plasma lipoproteins.

Evolutionary origins of apoB mRNA editing: catalysis by a cytidine deaminase that has acquired a novel RNA-binding motif at its active site.

https://www.cell.com/cell/pdf/0092-8674(89)90432-7.pdf

An in vitro system for the editing of apolipoprotein B mRNA

Sequence requirements for apolipoprotein B RNA editing in transfected rat hepatoma cells

Human apolipoprotein (apo)-B mRNA undergoes a novel tissue specific editing reaction which replaces a genomically templated cytidine with uridine. This substitution converts codon 2153 from glutamine (CAA) in apo-B100 mRNA to a stop codon (UAA) in apo-B48 mRNA. This novel RNA editing process is responsible for the generation of hepatic apo-B100 and intestinal apo-B48. We have established the following concerning this process: (1) by transfection of a series of deletion mutants into the rat hepatoma cell line McArdle 7777, which makes both apo-B100 and apo-B48, we have defined a minimum sequence of 26 nucleotides that is required for apo-B mRNA editing. The sequence containing the modified nucleotide forms a 26 nucleotide highly conserved stem loop with the modified nucleotide occurring in an 8-base loop. (2) Conversion in vitro of apo-B mRNA has been established, using cell free S100 cytoplasmic extract and synthetic RNA templates. Activity was abolished by protease treatment. (3) Transgenic mice were created which expressed a human apo-B construct spanning the stop codon. Apo-B mRNA was found in all tissues examined and this was shown to undergo editing. (4) In the rat liver, which produces apo B-100 and apo-B48, modulation of the relative proportion of these proteins by thyroxine was demonstrated to be mediated at the level of the RNA editing mechanism. It is concluded that apo-B mRNA is edited by a generally expressed protein and editing is highly regulated.

https://gut.bmj.com/content/gutjnl/30/Spec_No/35.full.pdf

RNA editing: a novel mechanism for regulating lipid transport from the intestine.

SUMMARY Humanapolipoprotein (apo)-B mRNA undergoes anovel tissue specific editing reaction whichreplaces agenomically templated cytidine withuridine. Thissubstitution converts codon2153 fromglutamine (CAA)inapo-B100 mRNA toa stopcodon(UAA)inapo-B48 mRNA.Thisnovel RNAediting processisresponsible forthegeneration ofhepatic apo-B100 andintestinal apo-B48. We haveestablished thefollowing concerning this process:(1)bytransfection ofa series ofdeletion mutantsinto therathepatoma cell line McArdle 7777, whichmakesbothapo-B100 andapo-B48, we havedefined a minimumsequenceof26nucleotides thatisrequired forapo-BmRNA editing. The sequencecontaining themodified nucleotide forms a26nucleotide highly conserved stemloopwith themodified nucleotide occurring inan 8-base loop. (2)Conversion invitro ofapo-BmRNA has beenestablished, using cell freeS100cytoplasmic extract andsynthetic RNA templates. Activity was abolished byprotease treatment. (3)Transgenic micewere created whichexpressed a human apo-Bconstruct spanning thestopcodon. Apo-BmRNA was foundinalltissues examined andthis was showntoundergoediting. (4)Intheratliver, whichproduces apo B-100andapo-B48, modulation oftherelative proportion ofthese proteins bythyroxine was demonstrated tobe mediated atthelevel oftheRNA editing mechanism. Itisconcluded thatapo-BmRNA isedited bya generally expressed protein andediting ishighly regulated.

RNA editing: anovel mechanism forregulating lipid transport fromtheintestine

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Sequence requirements for apolipoprotein B RNA editing in transfected rat hepatoma cells

RNA editing: a novel mechanism for regulating lipid transport from the intestine.

RNA editing: anovel mechanism forregulating lipid transport fromtheintestine