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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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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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