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Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157–1040
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ABSTRACT |
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 TOP ABSTRACT APOLIPOPROTEIN B IS ESSENTIAL...MICROSOMAL TRIGLYCERIDE TRANSFER...POST-TRANSCRIPTIONAL REGULATION...APO B HAS BEEN...SYSTEMATIC SCREENING OF APO...EVIDENCE THAT APO B...INITIATION OF APO...HYPOTHETICAL FUNCTIONS OF THE...REFERENCES |
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1 domain). When only
this domain is expressed in hepatoma cells, no lipoprotein particle
will form. However, proper folding of the 1 domain is
essential for the internal lipophilic regions of apoB to engage in
cotranslational lipid recruitment. The essential function of this
domain may be related to its capacity to promote a specific physical
interaction with the microsomal triglyceride transfer protein,
necessary for apoB's proper folding and lipidation. Alternatively,
this domain may promote an autonomous lipid recruitment step that
nucleates microsomal triglyceride transfer protein-dependent lipid
sequestration by apoB. Forms of apoB that fail to initiate particle
assembly or forms associated with aberrant underlipidated particles are
targeted for intracellular turnover. Two sites of apoB degradation have
been identified. In hepatocarcinoma-derived cells, misassembled apoB
may undergo progressive reverse translocation from the endoplasmic
reticulum lumen to the cytosol, a process that is mechanistically
coupled to polyubiquitination and proteasome-mediated degradation on
the cytosolic side of the membrane. Alternatively, studies in primary
hepatocytes reveal that apoB may undergo 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 hepatic VLDL.
KEY WORDS: • lipid acquisition • microsomal triglyceride transfer protein • protein domains • protein folding • proteosomes
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APOLIPOPROTEIN B IS ESSENTIAL FOR THE BIOGENESIS OF TRIGLYCERIDE-RICH VLDL |
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TOPABSTRACTAPOLIPOPROTEIN B IS ESSENTIAL...MICROSOMAL TRIGLYCERIDE TRANSFER...POST-TRANSCRIPTIONAL REGULATION...APO B HAS BEEN...SYSTEMATIC SCREENING OF APO...EVIDENCE THAT APO B...INITIATION OF APO...HYPOTHETICAL FUNCTIONS OF THE...REFERENCES |
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, Kane and Havel 1995
). Apolipoprotein B is a 4536-amino acid
secretory glycoprotein; in contrast to the class of soluble apoproteins
epitomized by apoA-I and apoE, it is insoluble in aqueous buffers.
Hence, apoB is incapable of exchanging among lipoprotein classes, and
its initial biosynthetic association with nascent VLDL particles that
occurs in the endoplasmic reticulum (ER) is considered irreversible.
Both experimental and theoretical considerations have provided a broad
framework for understanding the interactions of apoB with lipoprotein
lipids. Apolipoprotein B possesses a pentapartite structure in which
three domains dominated by amphipathic -helical structures
(1, 2 and 3) alternate
with two regions proposed to have a strong tendency to form
antiparallel amphipathic ß-strands (ß1 and
ß2) (Knott et al. 1986
, Schumaker et al. 1994
, Segrest et al. 1994
) (Fig. 1
).The amphipathic -helix is the basic lipid-binding unit of the class
of soluble apolipoproteins and is thought to confer strong but
reversible binding of apoB to the lipoprotein surface (Segrest et al. 1994
). The ß1 and ß2 domains may form a
series of amphipathic belt-like structures; the hydrophobic face of
these structures may interact directly with the triglyceride core
(Segrest et al. 1998
). The ß domains may be responsible for the
irreversible integration of apoB with lipoprotein lipids (Yang et al. 1989
).
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MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN IS A DEDICATED ENDOPLASMIC RETICULUM–LOCALIZED ASSEMBLY FACTOR REQUIRED FOR VLDL ASSEMBLY |
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TOPABSTRACTAPOLIPOPROTEIN B IS ESSENTIAL...MICROSOMAL TRIGLYCERIDE TRANSFER...POST-TRANSCRIPTIONAL REGULATION...APO B HAS BEEN...SYSTEMATIC SCREENING OF APO...EVIDENCE THAT APO B...INITIATION OF APO...HYPOTHETICAL FUNCTIONS OF THE...REFERENCES |
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). Abetalipoproteinemia is a syndrome that is
phenotypically similar to severe homozygous hypobetalipoproteinemia,
but is not caused by defects in the apoB gene (Tamud et al. 1988
).
Using a candidate gene approach, Gregg, Wetterau and colleagues (Sharp et al. 1993
) discovered that the absence of apoB-containing
lipoproteins in abetalipoproteinemia is caused by mutations in the gene
for the large subunit of microsomal triglyceride transfer protein
(MTP).
Microsomal triglyceride transfer protein was first identified
biochemically as a neutral lipid transfer activity localized to the
lumen of the endoplasmic reticulum (ER). Its expression is limited to
the liver and intestine, the only two tissues that express large
amounts of apoB (Wetterau and Zilversmit 1986
). Purification of MTP
revealed a heterodimer composed of a unique 97-kDa subunit complexed
with the ubiquitous ER-localized chaperone/folding enzyme, protein
disulfide isomerase (PDI) (Wetterau et al. 1990
). The discovery of MTP
gene defects associated with abetalipoproteinemia provided the first
direct evidence that MTP is essential for the assembly and secretion of
apoB-containing lipoproteins. This requirement can also be demonstrated
experimentally, i.e., when forms of apoB longer than approximately the
length of apoB-28 are transfected into a cell line lacking MTP, the
protein is synthesized but does not undergo appreciable secretion.
However, if the large subunit of MTP is cotransfected along with apoB,
the process of lipoprotein assembly is reconstituted, resulting in a
several-fold increase in buoyant apoB and triglyceride secretion
(Gordon et al. 1994
, Leiper et al. 1994
). The mechanism by which MTP
functions to promote apoB-containing lipoprotein assembly is not known
in detail. However, it is assumed, on the basis of its lipid transfer
activity, that MTP transfers lipid from the inner leaflet of the ER
membrane to apoB during its initial translation and translocation into
the ER (Gordon et al. 1995
). Other roles have been attributed to MTP,
including that of a factor essential for apoB translocation across the
ER membrane (Du et al. 1996
, see below) and possibly as a factor
required for the post-translational addition of triglyceride to apoB
(Alexander et al. 1976
, Rustaeus et al. 1998
, Wang et al. 1997
).
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POST-TRANSCRIPTIONAL REGULATION OF APO B SECRETION |
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TOPABSTRACTAPOLIPOPROTEIN B IS ESSENTIAL...MICROSOMAL TRIGLYCERIDE TRANSFER...POST-TRANSCRIPTIONAL REGULATION...APO B HAS BEEN...SYSTEMATIC SCREENING OF APO...EVIDENCE THAT APO B...INITIATION OF APO...HYPOTHETICAL FUNCTIONS OF THE...REFERENCES |
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, Dixon et al. 1991
, Sato et al. 1990
, White et al. 1992
). In
hepatoma cells, the proportion of apoB that is assembled into
secretion-competent lipoproteins can be regulated in several ways, but
appears ultimately to be determined by an intracellular pool of
secretion-coupled lipid (Wu et al. 1996a
). Oleic acid promotes apoB
secretion by stimulating triglyceride synthesis and availability (Dixon et al. 1991
, Wu et al. 1996a
), whereas (n-3) fatty acids inhibit apoB
secretion presumably by reducing the ability of hepatocytes to
synthesize or mobilize triglyceride for secretion (Wang et al. 1994
).
The relationship between apoB assembly and intracellular cholesterol
and cholesteryl ester mass and synthesis has been controversial, with
some investigators reporting a major regulatory role for the
intracellular cholesterol esterifying enzyme, acyl-CoA:cholesterol
acyltransferase (Cianflone et al. 1990
, Musanti et al. 1996
, Thompson et al. 1996
) and others observing that it is triglyceride synthesis
alone that drives lipoprotein secretion (Benoist and Grand-Perret 1996
,
Wu et al. 1994
). Finally, phosphatidylcholine synthesis is an important
potential regulator of apoB assembly and secretion (Yao and Vance 1988
). Irrespective of the effects of lipids and other factors on apoB
secretion, a prevailing view has emerged in which the apoB protein is
made in excess and directed toward a pool involved in both particle
assembly and secretion or intracellular degradation. The question of
how the cell is able to distinguish between these two pools of apoB has
important implications with respect to the regulation of VLDL
triglyceride secretion and the prevention and management of genetically
and environmentally induced hyperlipidemias. |
APO B HAS BEEN PROPOSED TO UNDERGO A REGULATED FORM OF TRANSLOCATION ACROSS THE ER MEMBRANE |
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TOPABSTRACTAPOLIPOPROTEIN B IS ESSENTIAL...MICROSOMAL TRIGLYCERIDE TRANSFER...POST-TRANSCRIPTIONAL REGULATION...APO B HAS BEEN...SYSTEMATIC SCREENING OF APO...EVIDENCE THAT APO B...INITIATION OF APO...HYPOTHETICAL FUNCTIONS OF THE...REFERENCES |
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). This generates a transmembrane form in which
the bulk of the protein mass is situated on the cytosolic side of the
ER membrane. It has been proposed that if lipid becomes available,
transmembrane apoB can undergo a process of post-translational
"lipid-facilitated translocation" into the lumen of the ER (Sakata et al. 1993
). However, if the translocation-arrested form of apoB
persists, it is targeted for degradation by the
ubiquitin/proteasome–mediated pathway in the cytosol (Fisher et al. 1997
, Yeung et al. 1996
). In large part, this model of regulated
translocation is based on the detection of transmembrane apoB by the
use of exogenous proteases that degrade putatively cytosolic domains of
apoB present in membrane-derived vesicles and permeabilized cells
(Davis et al. 1990
, Dixon et al. 1992
, Du et al. 1994 and 1998
, Macri and Adeli 1997
, Rusiñol et al. 1993
, Thrift et al. 1992
).
However, others have failed to confirm the existence of cytosolic apoB
(Ingram and Shelness 1996
, Leiper et al. 1996
, Pease et al. 1995
,
Shelness et al. 1994
, see below). |
SYSTEMATIC SCREENING OF APO B FOR DOMAINS CAPABLE OF REGULATING TRANSLOCATION |
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TOPABSTRACTAPOLIPOPROTEIN B IS ESSENTIAL...MICROSOMAL TRIGLYCERIDE TRANSFER...POST-TRANSCRIPTIONAL REGULATION...APO B HAS BEEN...SYSTEMATIC SCREENING OF APO...EVIDENCE THAT APO B...INITIATION OF APO...HYPOTHETICAL FUNCTIONS OF THE...REFERENCES |
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).
The interaction between the translating ribosome and the membrane can
be dynamic. Studies by Lingappa and colleagues (Chuck et al. 1990
,
Chuck and Lingappa 1992
) utilizing cell-free translation of apoB in the
presence of canine pancreas microsomes showed that the translocation of
apoB into membrane vesicles becomes transiently uncoupled from its
translation, thereby giving rise to cytoplasmic loops (Chuck et al. 1990
). The sequence domains responsible for this behavior were termed
"pause transfer" (Chuck and Lingappa 1992
) and were mapped to
multiple sites within apoB. Although the translocational pausing
observed in this system is transient, conditions were developed under
which apoB could be maintained in the paused condition for prolonged
periods of time. Under these conditions, the pausing of translocation
was accompanied by a disruption of the normally tight junction between
the ribosome and the ER membrane (Hegde and Lingappa 1996
). However,
when translocation of paused intermediates was restarted, complete
translocation of the nascent chain occurred. Hence, the translocation
of apoB in a cell-free system occurs efficiently, albeit in a fashion
that is not strictly coupled to translation.
The behavior of apoB in cell-free systems is distinct from the behavior
in cells in which, at steady state, the majority of apoB is putatively
found in a translocation-arrested form. Furthermore, the transmembrane
apoB in cells has never convincingly been shown to be a metabolic
precursor of fully translocated apoB (Du et al. 1998
, Macri and Adeli 1997
). In an attempt to identify structural features of apoB required
to achieve translocation arrest in cultured cells, a series of fusion
proteins were developed in which 300 amino acid overlapping segments of
apoB48 were appended to the amino-terminal 77 amino acids of a modified
form of bovine preprolactin (Shelness et al. 1994
). This strategy
enabled the preprolactin region of each construct (considered to be a
generic model secretory protein) to initiate ribosome targeting and
translocation before the emergence of the apoB test sequence from the
ribosome. The extent of translocation arrest or delay associated with
each segment of apoB could then be measured by treating ER-derived
membrane vesicles with exogenous protease and by examining the extent
to which glycosylation sites engineered into the N- and C-terminal
sides of the test sequences were utilized. On the basis of these
criteria (virtually complete resistance to protease and little
glycosylation heterogeneity), none of the apoB sequences was capable of
detectably delaying or arresting translocation in transfected COS-1
cells (an MTP-negative cell line) or HepG2 cells (Ingram and Shelness 1996
, Shelness et al. 1994
). These data demonstrated that neither pause
transfer nor any other isolated domain present in apoB48 was capable
singly of detectably delaying or arresting translocation in vivo.
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EVIDENCE THAT APO B DESTINED FOR LIPOPROTEIN ASSEMBLY OR INTRACELLULAR DEGRADATION UNDERGOES EFFICIENT TRANSLOCATION ACROSS THE ER MEMBRANE |
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TOPABSTRACTAPOLIPOPROTEIN B IS ESSENTIAL...MICROSOMAL TRIGLYCERIDE TRANSFER...POST-TRANSCRIPTIONAL REGULATION...APO B HAS BEEN...SYSTEMATIC SCREENING OF APO...EVIDENCE THAT APO B...INITIATION OF APO...HYPOTHETICAL FUNCTIONS OF THE...REFERENCES |
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, Du et al. 1994
). This is
similar to the amount of apoB that undergoes assembly into a secretable
lipoprotein (Dixon et al. 1991
) and is consistent with the idea that
successful translocation is observed only when apoB assembles with
lipids. However, when the percentage of transmembrane apoB in
unstimulated HepG2 cells was systematically studied with the use of a
protease protection assay, the mean percentage protection was 84 ± 18 (n = 14), a value similar to that observed for
several control secretory proteins (Ingram and Shelness 1996
, Leiper et al. 1996
). Furthermore, no significant difference in protease
protection was observed in control cells or cells treated with
N-acetyl-Leu-Leu-norleucinal (ALLN).
N-Acetyl-Leu-Leu-norleucinal is a tripeptide derivative that
inhibits a variety of cysteine proteases, including the cytoplasmic
proteasome (Coux et al. 1996
). Because it has been proposed that the
substrate for the ALLN-inhibitable protease is the
translocation-arrested form of apoB (Bonnardel and Davis 1995
, Sakata et al. 1993
, Thrift et al. 1992
, Yeung et al. 1996
), one should see a
relative increase in transmembrane apoB in ALLN-treated cells. However,
despite a sixfold increase in the amount of intracellular apoB in
ALLN-treated vs. control cells, the percentage of protease-resistant
apoB remained uniformly high (Ingram and Shelness 1996
). These results
suggest that apoB destined for intracellular assembly into lipoprotein
particles or destined for intracellular degradation by the
ALLN-sensitive proteolytic system are both efficiently translocated
into the ER lumen.
If apoB is efficiently translocated into the ER, how does it become
exposed to the cytosolic proteasome? A general pathway for the disposal
of misfolded secretory proteins at the level of the ER has been
described recently. Surprisingly, these proteins appear to undergo a
retrograde translocation (dislocation) reaction from the ER lumen to
the cytosol (Hiller et al. 1996
, Qu et al. 1996
). Apolipoprotein B may
therefore undergo complete translocation into the ER followed by either
a co- or post-translational dislocation of all or part of the apoB
polypeptide chain into the cytosol (Fig. 2
).The fact that this process generates little detectable transmembrane
apoB indicates that the dislocation reaction may be temporally and
mechanistically coupled to proteasome-mediated degradation (Kopito 1997
). Although the disposal of apoB in hepatocarcinoma-derived cell
lines appears to occur predominantly at the level of the ER, apoB
turnover in primary rat hepatocytes may involve vesicular sorting to a
post-ER compartment (Wang et al. 1995
). In either case, the balance
between assembly and presecretory degradation may represent a major
control point for the production of hepatic VLDL.
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INITIATION OF APO B–CONTAINING LIPOPROTEIN ASSEMBLY: ROLE OF
THE 1 DOMAIN
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TOPABSTRACTAPOLIPOPROTEIN B IS ESSENTIAL...MICROSOMAL TRIGLYCERIDE TRANSFER...POST-TRANSCRIPTIONAL REGULATION...APO B HAS BEEN...SYSTEMATIC SCREENING OF APO...EVIDENCE THAT APO B...INITIATION OF APO...HYPOTHETICAL FUNCTIONS OF THE...REFERENCES |
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, Spring et al. 1992
). The same relationship between apoB
length and lipoprotein size was observed for a series of C-terminally
truncated forms of apoB expressed in rat hepatoma cells (Graham et al. 1991
, McLeod et al. 1994
, Yao et al. 1991
). However, this relationship
applies only in the size range between apoB-25 and -100. Forms of apoB
containing less than the amino-terminal ~25% of the protein do not
require MTP or assembly with lipid to achieve secretion competence and
are recovered from transfected cell media in lipid-poor form.
Although the initial formation of apoB-containing lipoproteins may
occur cotranslationally, virtually nothing is known of how the initial
folding of apoB and its interactions with MTP, lipids, the ER membrane
and ER-associated chaperones initiate this process. Because it is the
first domain to enter the ER, considerable attention was focused on the
structure and function of the globular 1 domain of apoB.
As outlined above and diagrammed in Figure 1
, apoB has been described
in terms of a pentapartite structure in which three amphipathic
-helical domains alternate with two domains proposed to form
amphipathic ß-sheet structures. Interestingly, the 1
domain possesses the following properties distinct from those of the
rest of the apoB protein: 1) it is globular and highly
disulfide bonded [6 of the 8 disulfide bonds in apoB-100 are
positioned within the amino-terminal 11% of the protein (Yang et al. 1990
)]; 2) it demonstrates a lower affinity for plasma LDL
particle than internal and carboxyl-terminal domains (Chan 1992
,
Segrest et al. 1994
); and 3) in transfected cells, forms of
apoB containing only the 1 domain (e.g., apoB-18) lack
the capacity to recruit a significant amount of lipid and can be
secreted independently of MTP (Graham et al. 1991
, Yao et al. 1991
).
Because of the asymmetric distribution of disulfide bonds in the
1 domain, the thiol-reducing agent dithiothreitol was
used to perturb its folding and assess the effects on the capacity of
apoB to initiate lipoprotein formation (Ingram and Shelness 1997
,
Shelness and Thornburg 1996
). These studies revealed the following
features of 1 domain that are relevant to understanding
how apoB-containing lipoprotein assembly may be initiated:
1) The 1 domain of apoB was observed to fold
during the process of translation, consistent with a domain-specific
folding reaction that is completed before the translation and
translocation of the more internal lipophilic regions of apoB (i.e.,
the ß1 domain). 2) The cotranslational folding
of the 1 domain occurred to a similar extent and with
similar kinetics in both hepatoma and Chinese hamster ovary (CHO)
cells, which lack MTP. Therefore, the folding of this domain is
achieved independently of MTP and before events associated with buoyant
lipoprotein formation. 3) Forms of apoB in which folding of
the 1 domain was blocked were incapable of undergoing
detectable assembly with lipid. Hence, in addition to its unique
structural properties and folding kinetics, the amino terminal
1 region of apoB was indeed shown to be essential to
initiate lipoprotein formation in the ER.
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HYPOTHETICAL FUNCTIONS OF THE 1 DOMAIN OF APO B IN
THE INITIATION OF LIPOPROTEIN ASSEMBLY
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TOPABSTRACTAPOLIPOPROTEIN B IS ESSENTIAL...MICROSOMAL TRIGLYCERIDE TRANSFER...POST-TRANSCRIPTIONAL REGULATION...APO B HAS BEEN...SYSTEMATIC SCREENING OF APO...EVIDENCE THAT APO B...INITIATION OF APO...HYPOTHETICAL FUNCTIONS OF THE...REFERENCES |
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demonstrated that
apoB-17 can bind to dimyristoylphosphatidylcholine multilamellar
vesicles and convert them to discoidal recombinant lipoproteins in
vitro. In addition, apoB-15, translated in vitro in the presence of rat
liver microsomes, undergoes association with newly synthesized
phosphatidylcholine (Rusiñol et al. 1997
). Hence, one potential
function of the 1 domain may be to recruit a
phospholipid surface early in translation that would then serve as an
acceptor site for MTP-mediated lipid transfer (lower right corner
of Fig. 3).The subsequent delivery of neutral lipid to this site, concomitant with
the translation and translocation of the internal lipophilic regions of
apoB into the ER, would drive the formation of a primordial
core-containing lipoprotein, akin to the maturation of discoidal HDL to
spherical HDL (Hamilton et al. 1976
, Tall and Small 1978
). Another
potential function of the 1 domain of apoB may be to
associate with the inner leaflet of the ER membrane. This association
may initiate formation of a triglyceride droplet (Fig. 3
, upper right
corner). At some point during or after translation, this droplet may
bud from the membrane into the lumen of the ER (Atkinson and Small 1986
, Olofsson et al. 1987
, Schumaker et al. 1994
). In support of this
model, Pease et al. (1991)
showed that during cell-free translation in
the presence of dog pancreas microsomes, apoB-17 translocates into the
inner leaflet of the ER membrane in a form that cannot be extracted
with sodium carbonate, pH 11.5. Yet another potential function of the
1 domain of apoB is to provide a binding site for MTP
(Fig. 3
, upper left corner). Wu et al. (1996b)
demonstrated that MTP is
physically associated with apoB during lipoprotein assembly in the ER
on the basis of co-immunoprecipitation of both apoB and MTP with
antibodies directed against either of the two proteins. Microsomal
triglyceride transfer protein interacts with forms of apoB containing
as little as the amino-terminal ~17% of the protein (Hussain et al. 1997
, Patel and Grundy 1996
). These studies indicate that apoB may
engage MTP at an early stage of its translation and that this
interaction is critical to achieve net lipid transfer to apoB during
its translation and/or to serve as a chaperone for critical folding and
assembly events necessary for lipoprotein particle assembly (Fig. 3
,
upper left panel).
|
1 domain of apoB
diagrammed in Figure 3
and discussed above are intriguing, their
relationship to the mechanism of apoB-containing lipoprotein assembly
remains speculative. A molecular description of this process awaits the
development of more detailed structural and functional characterization
of the apoB protein, a task that is currently underway in several
laboratories.
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FOOTNOTES |
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1 Presented at the symposium "Assembly and
Physiology of Apolipoprotein B-Containing Lipoproteins It's Not Just
for Heart Disease Anymore!" as part of Experimental Biology 98, April
18–22, 1998, San Francisco, CA. The symposium was sponsored by the
Energy and Macronutrient Research Interest Section of the American
Society for Nutritional Sciences, the Egg Nutrition Center, the
American Heart Association-Western States Affiliate, Merck Research
Laboratories, Bristol-Meyers Squibb Pharmaceutical Research Institute
and Parke-Davis Pharmaceutical Research. Published as a supplement to
The Journal of Nutrition. Guest editors for this supplement
were Rosemary L. Walzem, University of California, Davis, and Robert L.
Hamilton, University of California, San Francisco, CA.
2 Supported by National Institutes of Health Grant
HL49373 and an established Investigatorship from the American Heart
Association.
3 Abbreviations used: ALLN,
N-acetyl-Leu-Leu-norleucinal; apo, apolipoprotein; ER,
endoplasmic reticulum; MTP, microsomal triglyceride transfer protein;
PDI, protein disulfide isomerase.
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REFERENCES |
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TOPABSTRACTAPOLIPOPROTEIN B IS ESSENTIAL...MICROSOMAL TRIGLYCERIDE TRANSFER...POST-TRANSCRIPTIONAL REGULATION...APO B HAS BEEN...SYSTEMATIC SCREENING OF APO...EVIDENCE THAT APO B...INITIATION OF APO...HYPOTHETICAL FUNCTIONS OF THE...REFERENCES |
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1.
Alexander C. A., Hamilton R. L., Havel R. J.. Subcellular localization of B apoprotein of plasma lipoproteins in rat liver. J. Cell Biol. 1976;69:241-263.
2. Atkinson D., Small D. M.. Recombinant lipoproteinsimplications for structure and assembly of native lipoproteins. Annu. Rev. Biophys. Chem. 1986;15:403-456.[Medline]
3.
Benoist F., Grand-Perret T.. ApoB-100 secretion by HepG2 cells is regulated by the rate of triglyceride biosynthesis but not by intracellular lipid pools. Arterioscler. Thromb. Vasc. Biol. 1996;16:1229-1235.
4.
Benoist F., Grand-Perret T.. Co-translational degradation of apolipoprotein B100 by the proteasome is prevented by microsomal triglyceride transfer proteinSynchronized translation studies on HepG2 cells treated with an inhibitor of microsomal triglyceride transfer protein. J. Biol. Chem. 1997;272:20435-20442.
5.
Bonnardel J. A., Davis R. A.. In HepG2 cells, translocation, not degradation, determines the fate of the de novo synthesized apolipoprotein B. J. Biol. Chem. 1995;270:28892-28896.
6.
Borchardt R. A., Davis R. A.. Intrahepatic assembly of very low density lipoproteinsrate of transport out of the endoplasmic reticulum determines rate of secretion. J. Biol. Chem. 1987;262:16394-16402.
7. Borén J., Graham L., Wettesten M., Scott J., White A., Olofsson S.-O.. The assembly and secretion of ApoB 100-containing lipoproteins in Hep G2 cells. ApoB 1992;100 is cotranslationally integrated into lipoproteins. J. Biol. Chem. 267:9858-9867.
8.
Chan L.. Apolipoprotein B, the major protein component of triglyceride-rich and low density lipoproteins. J. Biol. Chem. 1992;267:25621-25624.
9. Chuck S. L., Lingappa V. R.. Pause transfera topogenic sequence in apolipoprotein B mediates stopping and restarting of translocation. Cell 1992;68:9-21.[Medline]
10. Chuck S. L., Yao Z., Blackhart B. D., McCarthy B. J., Lingappa V. R.. New variations on the translocation of proteins during early biogenesis of apolipoprotein B. Nature (Lond.) 1990;346:382-385.[Medline]
11. Cianflone K. M., Yasruel Z., Rodriguez M. A., Vas D., Sniderman A. D.. Regulation of apoB secretion from HepG2 cellsevidence for a critical role for cholesteryl ester synthesis in the response to a fatty acid challenge. J. Lipid Res. 1990;31:2045-2055.[Abstract]
12. Coux O., Tanaka K., Goldberg A. L.. Structure and functions of the 20S and 26S proteasomes. Metheds Enzymol 1996;65:801-847.
13.
Davis R. A., Thrift R. N., Wu C. C., Howell K. E.. Apolipoprotein B is both integrated into and translocated across the endoplasmic reticulum membrane. J. Biol. Chem. 1990;265:10005-10011.
14.
Dixon J. L., Chattapadhyay T., Huima T., Redman C. M., Banerjee D.. Biosynthesis of lipoproteinslocation of nascent apoAI and apoB in the rough endoplasmic reticulum of chicken hepatocytes. J. Cell Biol. 1992;117:1161-1169.
15.
Dixon J. L., Furukawa S., Ginsberg H. N.. Oleate stimulates secretion of apolipoprotein B-containing lipoproteins from Hep G2 cells by inhibiting early intracellular degradation of apolipoprotein B. J. Biol. Chem. 1991;266:5080-5086.
16.
Du E. Z., Kurth J., Wang S.-L., Humiston P., Davis R. A.. Proteolysis-coupled secretion of the N terminus of apolipoprotein BCharacterization of a transient, translocation arrested intermediate. J. Biol. Chem. 1994;269:24169-24176.
17. Du E. Z., Wang S. L., Kayden H. J., Sokol R., Curtiss L. K., Davis R. A.. Translocation of apolipoprotein B across the endoplasmic reticulum is blocked in abetalipoproteinemia. J. Lipid Res. 1996;37:1309-1315.[Abstract]
18.
Du X. B., Stoops J. D., Mertz J. R., Stanley C. M., Dixon J. L.. Identification of two regions in apolipoprotein B 100 that are exposed on the cytosolic side of the endoplasmic reticulum membrane. J. Cell Biol. 1998;141:585-599.
19.
Fisher E. A., Zhou M., Mitchell D. M., Wu X., Omura S., Wang H., Goldberg A. L., Ginsberg H. N.. The degradation of apolipoprotein B100 is mediated by the ubiquitin-proteasome pathway and involves heat shock protein 70. J. Biol. Chem. 1997;272:20427-20434.
20.
Gordon D. A., Jamil H., Sharp D., Mullaney D., Yao Z., Gregg R. E., Wetterau J.. Secretion of apolipoprotein B-containing lipoproteins from HeLa cells is dependent on expression of the microsomal triglyceride transfer protein and is regulated by lipid availability. Proc. Natl. Acad. Sci. U.S.A . 1994;91:7628-7632.
21. Gordon D. A., Wetterau J. R., Gregg R. E.. Microsomal triglyceride transfer proteina protein complex required for the assembly of lipoprotein particles. Trends Cell Biol 1995;5:317-321.[Medline]
22. Graham D. L., Knott T. J., Jones T. C., Pease R. J., Pullinger C. R., Scott J.. Carboxyl-terminal truncation of apolipoprotein B results in gradual loss of the ability to form buoyant lipoproteins in cultured human and rat liver cell lines. Biochemistry 1991;30:5616-5621.[Medline]
23.
Gretch D. G., Sturley S. L., Wang L., Lipton B. A., Dunning A., Grunwald K.A.A., Wetterau J. R., Yao Z. M., Talmud P., Attie A. D.. The amino terminus of apolipoprotein B is necessary but not sufficient for microsomal triglyceride transfer protein responsiveness. J. Biol. Chem. 1996;271:8682-8691.
24. Hamilton R. L., Williams M. C., Fielding C. J., Havel R. J.. Discoidal bilayer structure of nascent high density lipoproteins from perfused rat liver. J. Clin. Investig. 1976;58:667-680.
25. Hegde R. S., Lingappa V. R.. Sequence-specific alterations of the ribosome-membrane junction expose nascent secretory proteins to the cytosol. Cell 1996;85:217-228.[Medline]
26.
Herscovitz H., Hadzopoulou-Cladaras M., Walsh M. T., Cladaras C., Zannis V. I., Small D. M.. Expression, secretion, and lipid-binding characterization of the N-terminal 17% of apolipoprotein B. Proc. Natl. Acad. Sci. U.S.A. 1991;88:7313-7317.
27.
Hiller M. M., Finger A., Schweiger M., Wolf D. H.. ER degradation of a misfolded luminal protein by the cytosolic ubiquitin-proteasome pathway. Science (Washington, DC) 1996;273:1725-1728.
28.
Homanics G. E., Smith T. J., Zhang S. H., Lee D., Young S. G., Maeda N.. Targeted modification of the apolipoprotein B gene results in hypobetalipoproteinemia and developmental abnormalities in mice. Proc. Natl. Acad. Sci. U.S.A. 1993;90:2389-2393.
29.
Huang X. F., Shelness G. S.. Identification of cysteine pairs within the amino-terminal 5% of apolipoprotein B essential for hepatic lipoprotein assembly and secretion. J. Biol. Chem. 1997;272:31872-31876.
30. Hussain M. M., Bakillah A., Jamil H.. Apolipoprotein B binding to microsomal triglyceride transfer protein decreases with increases in length and lipidationimplications in lipoprotein biosynthesis. Biochemistry 1997;36:13060-13067.[Medline]
31. Ingram M. F., Shelness G. S.. Apolipoprotein B-100 destined for lipoprotein assembly and intracellular degradation undergoes efficient translocation across the endoplasmic reticulum membrane. J. Lipid Res. 1996;37:2202-2214.[Abstract]
32.
Ingram M. F., Shelness G. S.. Folding of the amino-terminal domain of apolipoprotein B initiates microsomal triglyceride transfer protein-dependent lipid transfer to nascent very low density lipoprotein. J. Biol. Chem. 1997;272:10279-10286.
33. Johnson A. E., Liao S., Lin J., Hamman B., Do H., Cowie A., Andrews D. W.. The environment of nascent secretory and membrane proteins at the endoplasmic reticulum membrane during translocation and integrationCold Spring Harbor Symp. Quant. Biol. 1995;60:71-82.
34. Kane J. P., Havel R. J.. Disorders of the biogenesis and secretion of lipoproteins containing the B apolipoproteins. Scriver C. R. Beaudet A. L. Sly W. S. Valle D. eds. The Metabolic Basis of Inherited Disease 1995:1139-1163 McGraw-Hill New York, NY.. .
35. Knott T. J., Pease R. J., Powell L. M., Wallis S. C, Rall S. C., Jr, Innerarity T. L., Blackhart B., Taylor W. H., Marcel Y., Milne R., Johnson D., Fuller M., Lusis A. J., McCarthy B. J., Mahley R. W., Levy-Wilson B., Scott J.. Complete protein sequence and identification of structural domains of human apolipoprotein B. Nature (Lond.) 1986;323:734-738.[Medline]
36. Kopito R. R.. ER quality controlthe cytoplasmic connection. Cell 1997;88:427-430.[Medline]
37.
Leiper J. M., Bayliss J. D., Pease R. J., Brett D. J., Scott J., Shoulders C. C.. Microsomal triglyceride transfer protein, the abetalipoproteinemia gene product, mediates the secretion of apolipoprotein B-containing lipoproteins from heterologous cells. J. Biol. Chem. 1994;269:21951-21954.
38. Leiper J. M., Harrison G. B., Bayliss J. D., Scott J., Pease R. J.. Systematic expression of the complete coding sequence of apoB-100 does not reveal transmembrane determinants. J. Lipid Res. 1996;37:2215-2231.[Abstract]
39. Linton M. F., Farese R. V., Jr, Young S. G.. Familial hypobetalipoproteinemia. J. Lipid Res. 1993;34:521-541.[Medline]
40.
Macri J., Adeli K.. Studies on intracellular translocation of apolipoprotein B in a permeabilized HepG2 system. J. Biol. Chem. 1997;272:7328-7337.
41.
McLeod R. S., Yang Z., Selby S. L., Westerlund J., Yao Z.. Carboxyl-terminal truncation impairs lipid recruitment by apolipoprotein B100 but does not affect secretion of the truncated apolipoprotein B-containing lipoproteins. J. Biol. Chem. 1994;269:2852-2862.
42. Musanti R., Giorgini L., Lovisolo P., Pirillo A., Chiari A., Ghiselli G.. Inhibition of acyl-CoA:cholesterol acyltransferase decreases apolipoprotein B-100-containing lipoprotein secretion from HepG2 cells. J. Lipid Res. 1996;37:1-14.[Abstract]
43. Olofsson S.-O., Bjursell G., Boström K., Carlsson P., Elovson J., Protter A. A., Reuben M., A & Bondjers G.. Apolipoprotein Bstructure, biosynthesis and role in the lipoprotein assembly process. Atherosclerosis 1987;68:1-17.[Medline]
44.
Patel S. B., Grundy S. M.. Interactions between microsomal triglyceride transfer protein and apolipoprotein B within the endoplasmic reticulum in a heterologous expression system. J. Biol. Chem. 1996;271:18686-18694.
45. Pease R. J., Harrison G. B., Scott J.. Cotranslocational insertion of apolipoprotein B into the inner leaflet of the endoplasmic reticulum. Nature (Lond.) 1991;353:448-450.[Medline]
46.
Pease R. J., Leiper J. M., Harrison G. B., Scott J.. Studies on the translocation of the amino terminus of apolipoprotein B into the endoplasmic reticulum. J. Biol. Chem. 1995;270:7261-7271.
47.
Qu D. F., Teckman J. H., Omura S., Perlmutter D. H.. Degradation of a mutant secretory protein, 1-antitrypsin Z, in the endoplasmic reticulum requires proteasome activity. J. Biol. Chem. 1996;271:22791-22795.
48.
Rusiñol A. E., Chan E.Y.W., Vance J. E.. Movement of apolipoprotein B into the lumen of microsomes from hepatocytes is disrupted in membranes enriched in phosphatidylmonomethylethanolamine. J. Biol. Chem. 1993;268:25168-25175.
49.
Rusiñol A. E., Jamil H., Vance J. E.. In vitro reconstitution of assembly of apolipoprotein B48-containing lipoproteins. J. Biol. Chem. 1997;272:8019-8025.
50.
Rustaeus S., Stillemark P., Lindberg K., Gordon D., Olofsson S. O.. The microsomal triglyceride transfer protein catalyzes the post-translational assembly of apolipoprotein B-100 very low density lipoprotein in McA-RH7777 cells. J. Biol. Chem. 1998;273:5196-5203.
51.
Sakata N., Wu X., Dixon J. L., Ginsberg H. N.. Proteolysis and lipid-facilitated translocation are distinct but competitive processes that regulate secretion of apolipoprotein B in HepG2 cells. J. Biol. Chem. 1993;268:22967-22970.
52.
Sato R., Imanaka T., Takatsuki A., Takano T.. Degradation of newly synthesized apolipoprotein B-100 in pre-Golgi compartment. J. Biol. Chem. 1990;265:11880-11884.
53. Schumaker V. N., Phillips M. L., Chatterton J. E.. Apolipoprotein B and low-density lipoprotein structureimplications for biosynthesis of triglyceride-rich lipoproteins. Adv. Protein Chem. 1994;45:205-248.[Medline]
54.
Segrest J. P., Jones M. K., Mishra V. K., Anantharamaiah G. M., Garber D. W.. ApoB-100 has a pentapartite structure composed of three amphipathic -helical domains alternating with two amphipathic ß-strand domainsdetection by the computer program LOCATE. Arterioscler. Thromb. 1994;14:1674-1685.
55.
Segrest J. P., Jones M. K., Mishra V. K., Pierotti V., Young S. H., Borén J., Innerarity T. L., Dashti N.. Apolipoprotein B-100conservation of lipid-associating amphipathic secondary structural motifs in nine species of vertebrates. J. Lipid Res. 1998;39:85-102.
56. Sharp D., Blinderman L., Combs K. A., Kienzle B., Ricci B., Wager-Smith K., Gil C. M., Turck C. W., Bouma M.-E., Rader D. J., Aggerbeck L. P., Gregg R. E., Gordon D. A., Wetterau J. R.. Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinemia. Nature (Lond.) 1993;365:65-69.[Medline]
57.
Shelness G. S., Morris-Rogers K. C., Ingram M. F.. Apolipoprotein B48-membrane interactionsAbsence of transmembrane localization in nonhepatic cells. J. Biol. Chem. 1994;269:9310-9318.
58. Shelness G. S., Thornburg J. T.. Role of intramolecular disulfide bond formation in the assembly and secretion of apolipoprotein B-100-containing lipoproteins. J. Lipid Res. 1996;37:408-419.[Abstract]
59.
Spring D. J., Chen-Liu L. W., Chatterton J. E., Elovson J., Schumaker V. N.. Lipoprotein assemblyApolipoprotein B size determines lipoprotein core circumference. J. Biol. Chem. 1992;267:14839-14845.
60. Tall A. R., Small D. M.. Plasma high-density lipoproteins. N. Engl. J. Med. 1978;299:1232-1236.[Medline]
61. Tamud P. J., Lloyd J. K., Muller D.P.R., Collins D. R., Scott J., Humphries S.. Genetic evidence from two families that the apolipoprotein B gene is not involved in abetalipoproteinemia. J. Clin. Investig. 1988;82:1803-1806.
62. Thompson G. R., Naoumova R. P., Watts G. F.. Role of cholesterol in regulating apolipoprotein B secretion by the liver. J. Lipid Res. 1996;37:439-447.[Abstract]
63.
Thrift R. N., Drisko J., Dueland S., Trawick J. D., Davis R. A.. Translocation of apolipoprotein B across the endoplasmic reticulum is blocked in a nonhepatic cell line. Proc. Natl. Acad. Sci. U.S.A. 1992;89:9161-9165.
64.
Tran K., Borén J., Macri J., Wang Y., McLeod R., Avramoglu R. K., Adeli K., Yao Z.. Functional analysis of disulfide linkages clustered within the amino terminus of human apolipoprotein B. J. Biol. Chem. 1998;273:7244-7251.
65.
Wang C. N., Hobman T. C., Brindley D. N.. Degradation of apolipoprotein B in cultured rat hepatocytes occurs in a post-endoplasmic reticulum compartment. J. Biol. Chem. 1995;270:24924-24931.
66.
Wang H., Yao Z., Fisher E. A.. The effects of n-3 fatty acids on the secretion of carboxyl-terminally truncated forms of human apoprotein B. J. Biol. Chem. 1994;269:18514-18520.
67.
Wang Y., McLeod R. S., Yao Z.. Normal activity of microsomal triglyceride transfer protein is required for the oleate-stimulated secretion of very low density lipoproteins containing apolipoprotein B from McA-RH7777 cells. J. Biol. Chem. 1997;272:12272-12278.
68. Wetterau J. R., Combs K. A., Spinner S. N., Joiner B. J.. Protein disulfide isomerase is a component of the microsomal triglyceride transfer protein complex. J. Biol. Chem. 1990;265:9800-9807.
69. Wetterau J. R., Zilversmit D. B.. Localization of intracellular triacylglycerol and cholesteryl ester transfer activity in rat tissues. Biochim. Biophys. Acta 1986;875:610-617.[Medline]
70.
White A. L., Graham D. L., LeGros J., Pease R. J., Scott J.. Oleate-mediated stimulation of apolipoprotein B secretion from rat hepatoma cellsA function of the ability of apolipoprotein B to direct lipoprotein assembly and escape presecretory degradation. J. Biol. Chem. 1992;267:15657-15664.
71.
Wu X., Sakata N., Lui E., Ginsberg H. N.. Evidence for a lack of regulation of the assembly and secretion of apolipoprotein B-containing lipoprotein from HepG2 cells by cholesteryl ester. J. Biol. Chem. 1994;269:12375-12382.
72. Wu X. J., Shang A. M., Jiang H. S., Ginsberg H. N.. Low rates of apoB secretion from HepG2 cells result from reduced delivery of newly synthesized triglyceride to a "secretion-coupled" pool. J. Lipid Res. 1996;37:1198-1206.[Abstract]
73.
Wu X. J., Zhou M. Y., Huang L. S., Wetterau J., Ginsberg H. N.. Demonstration of a physical interaction between microsomal triglyceride transfer protein and apolipoprotein B during the assembly of ApoB-containing lipoproteins. J. Biol. Chem. 1996;271:10277-10281.
74.
Yang C.-Y., Gu Z.-W., Weng S.-A., Kim T. W., Chen S.-H., Pownall H. J., Sharp P. M., Liu S.-W., Li W.-H., Gotto A. M., Jr, Chan L.. Structure of apolipoprotein B-100 of human low density lipoprotein. Arteriosclerosis 1989;9:96-108.
75.
Yang C.-Y., Kim T. W., Weng S.-A., Lee B, Yang M., Gotto A. M., Jr. Isolation and characterization of sulfhydryls and disulfide peptides of human apolipoprotein B-100. Proc. Natl. Acad. Sci. U.S.A. 1990;87:5523-5527.
76.
Yao Z., Blackhart B. D., Linton M. F., Taylor S. M., Young S. G., McCarthy B. J.. Expression of carboxyl-terminally truncated forms of human apolipoprotein B in rat hepatoma cellsEvidence that the length of apolipoprotein B has a major effect on the buoyant density of the secreted lipoproteins. J. Biol. Chem. 1991;266:3300-3308.
77.
Yao Z., Vance D. E.. The active synthesis of phosphatidylcholine is required for very low density lipoprotein secretion from rat hepatocytes. J. Biol. Chem. 1988;263:2998-3004.
78. Yeung S. J., Chen S. H., Chan L.. Ubiquitin-proteasome pathway mediates intracellular degradation of apolipoprotein B. Biochemistry 1996;35:13843-13848.[Medline]
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