A Common Binding Site on the Microsomal Triglyceride Transfer Protein for Apolipoprotein B and Protein Disulfide Isomerase

Bradbury, Paul; Mann, Christopher; Köchl, Silvano; Anderson, Timothy A.; Chester, Sean; Hancock, John M.; Ritchie, Penelope J.; Amey, Joanna S.; Harrison, Georgina B.; Levitt, David G.; Banaszak, Leonard J.; Scott, James; Shoulders, Carol C.

doi:10.1074/jbc.274.5.3159

Cited by 91 publications

(77 citation statements)

References 23 publications

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“…Second, the laboratory of Mahmood Hussain has provided biochemical evidence that MTP binds to apoB (9) and that this interaction depends on arginine and lysine residues within apoB (10). Third, a pair of recent studies, each using independent experimental approaches, identified specific domains within the amino terminus of apoB that bind to the 97-kDa subunit of MTP (11,12). It has been suggested that apoB-MTP complexes could play an important role in the assembly of apoB-containing lipoproteins (12,13).…”

Section: Microsomal Triglyceride Transfer Protein (Mtp)mentioning

confidence: 99%

“…Third, a pair of recent studies, each using independent experimental approaches, identified specific domains within the amino terminus of apoB that bind to the 97-kDa subunit of MTP (11,12). It has been suggested that apoB-MTP complexes could play an important role in the assembly of apoB-containing lipoproteins (12,13).To define the role of MTP in lipoprotein assembly in vivo, our laboratory recently inactivated the mouse gene for the 97-kDa subunit of MTP (Mttp) (4). Homozygous Mttp knockout mice died early in development, likely because an absence of lipoprotein secretion by the yolk sac interferes with the delivery of lipid nutrients to the developing mouse embryo (4, 14).…”

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confidence: 99%

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A Deficiency of Microsomal Triglyceride Transfer Protein Reduces Apolipoprotein B Secretion

Leung¹,

Véniant²,

Kim³

et al. 2000

Journal of Biological Chemistry

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Microsomal triglyceride transfer protein (MTP) transfers lipids to apolipoprotein B (apoB) within the endoplasmic reticulum, a process that involves direct interactions between apoB and the large subunit of MTP. Recent studies with heterozygous MTP knockout mice have suggested that half-normal levels of MTP in the liver reduce apoB secretion. We hypothesized that reduced apoB secretion in the setting of half-normal MTP levels might be caused by a reduced MTP:apoB ratio in the endoplasmic reticulum, which would reduce the number of apoB-MTP interactions. If this hypothesis were true, half-normal levels of MTP might have little impact on lipoprotein secretion in the setting of halfnormal levels of apoB synthesis (since the ratio of MTP to apoB would not be abnormally low) and might cause an exaggerated reduction in lipoprotein secretion in the setting of apoB overexpression (since the MTP:apoB ratio would be even lower). To test this hypothesis, we examined the effects of heterozygous MTP deficiency on apoB metabolism in the setting of normal levels of apoB synthesis, half-normal levels of apoB synthesis (heterozygous Apob deficiency), and increased levels of apoB synthesis (transgenic overexpression of human apoB). Contrary to our expectations, half-normal levels of MTP reduced the plasma apoB100 levels to the same extent (ϳ25-35%) at each level of apoB synthesis. In addition, apoB secretion from primary hepatocytes was reduced to a comparable extent at each level of apoB synthesis. Thus, these results indicate that the concentration of MTP within the endoplasmic reticulum rather than the MTP:apoB ratio is the critical determinant of lipoprotein secretion. Finally, we found that heterozygosity for an apoB knockout mutation lowered plasma apoB100 levels more than heterozygosity for an MTP knockout allele. Consistent with that result, hepatic triglyceride accumulation was greater in heterozygous apoB knockout mice than in heterozygous MTP knockout mice. Microsomal triglyceride transfer protein (MTP)1 is expressed at high levels in the absorptive enterocytes of the intestine and hepatocytes, at moderate levels in the visceral endoderm of the yolk sac during embryonic development, and at relatively low levels in kidney and cardiac muscle (1-4). In each of these tissues, MTP plays a key role in the assembly and secretion of apoB-containing lipoproteins (1, 3, 5). MTP is located within the lumen of the endoplasmic reticulum (ER) and is thought to transfer lipids to apoB as that molecule is translated, allowing apoB to assume a proper conformation for forming a spherical lipoprotein with a neutral lipid core (6). In the absence of MTP, triglyceride-rich, apoB-containing lipoproteins cannot be assembled or secreted (3, 6, 7). The mechanism of MTP action has attracted considerable scrutiny. Of note, several lines of evidence have suggested that the assembly of lipoproteins involves a direct interaction between MTP and apoB. First, Wu et al. (8) demonstrated that apoB can be immunoprecipitated from the microsomes of cult...

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Section: Microsomal Triglyceride Transfer Protein (Mtp)mentioning

confidence: 99%

mentioning

confidence: 99%

A Deficiency of Microsomal Triglyceride Transfer Protein Reduces Apolipoprotein B Secretion

Leung¹,

Véniant²,

Kim³

et al. 2000

Journal of Biological Chemistry

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“…MTP catalyses the assembly of triglyceride-rich plasma lipoproteins (VLDL) and chylomicrons by carrying lipid from endoplasmic reticulum membrane to apoB particles in the lumen of endoplasmic reticulum (Olofsson et al 1999). The assembly of lipoproteins involves a physical binding of apoB and the larger subunit of MTP, but the precise mechanism remains to be elucidated (Bradbury et al 1999;Gretch et al 1996;Liang and Ginsberg 2001;Wetterau et al 1990).…”

Section: Introductionmentioning

confidence: 99%

Molecular screening of the microsomal triglyceride transfer protein: association between polymorphisms and both abdominal obesity and plasma apolipoprotein B concentration

et al. 2004

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Microsomal triglyceride transfer protein (MTP) plays a critical role in the assembly of lipoproteins. The aim of this study was first to seek new MTP gene variants and then to verify whether MTP gene polymorphisms were associated with plasma lipoprotein/lipid levels in men with visceral obesity. Molecular screening of the MTP gene revealed 11 polymorphisms. The carriers of the c.933A allele and c.1151C allele or À400A/A homozygotes were characterized by increased levels of abdominal visceral adipose tissue (AT) measured by computed tomography (P=0.02, P=0.04, P=0.03, respectively). After dividing each genotype group into subgroups using 130 cm 2 as a cutoff point for visceral AT, significantly higher low-density lipoprotein (LDL)-apolipoprotein B (apoB) concentrations were found in obese men bearing the c.891G allele, the À400 T allele, as well as for 282G/G homozygotes, 933C/C homozygotes, and 1151A/A homozygotes when compared to their lean counterparts. Haplotypes were not associated with phenotypes under study. In conclusion, some MTP gene polymorphisms in the French Canadian population are associated with the amount of abdominal visceral AT and plasma LDL-apoB concentrations.

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“…The 97-kDa subunit is expressed mainly in intestine and liver, and has the ability to catalyze the transfer of various lipids between lipid surfaces in vitro (12). Physical interaction between MTP and apoB has been observed (13)(14)(15)(16)(17)(18)(19), but it is not clear if MTP also catalyzes lipid transfer onto apoB in vivo. Inactivation of MTP in hepatic or intestinal cells invariably impairs apoB assembly and secretion (7,20,21).…”

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The Activity of Microsomal Triglyceride Transfer Protein Is Essential for Accumulation of Triglyceride within Microsomes in McA-RH7777 Cells

Wang¹,

Tran²,

Yao³

1999

Journal of Biological Chemistry

128

140

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Previously, based on distinct requirement of microsomal triglyceride transfer protein (MTP) and kinetics of triglyceride (TG) utilization, we concluded that assembly of very low density lipoproteins (VLDL) containing B48 or B100 was achieved through different paths (Wang, Y., McLeod, R. S., and Yao, Z. (1997) J. Biol. Chem. 272, 12272-12278). To test if the apparent dual mechanisms were accounted for by apolipoprotein B (apoB) length, we studied VLDL assembly using transfected cells expressing various apoB forms (e.g. B64, B72, B80, and B100). For each apoB, enlargement of lipoprotein to form VLDL via bulk TG incorporation was induced by exogenous oleate, which could be blocked by MTP inhibitor BMS-197636 treatment. While particle enlargement was readily demonstrable by density ultracentrifugation for B64-and B72-VLDL, it was not obvious for B80-and B100-VLDL unless the VLDL was further resolved by cumulative rate flotation into VLDL 1 (S f > 100) and VLDL 2 (S f 20 -100). BMS-197636 diminished B100 secretion in a dose-dependent manner (0.05-0.5 M) and also blocked the particle enlargement from small to large B100-lipoproteins. These results yield a unified model that can accommodate VLDL assembly with all apoB forms, which invalidates our previous conclusion. To gain a better understanding of the MTP action, we examined the effect of BMS-197636 on lipid and apoB synthesis during VLDL assembly. While BMS-197636 (0.2 M) entirely abolished B100-VLDL 1 assembly/secretion, it did not affect B100 translation or translocation across the microsomal membrane, nor did it affect TG synthesis and cell TG mass. However, BMS-197636 drastically decreased accumulation of [ 3 H]glycerol-labeled TG and TG mass within microsomal lumen. The decreased TG accumulation was not a result of impaired B100-VLDL assembly, because in cells treated with brefeldin A (0.2 g/ml), the assembly of B100-VLDL was blocked yet lumenal TG accumulation was normal. Thus, MTP plays a role in facilitating accumulation of TG within microsomes, a prerequisite for the post-translational assembly of TG-enriched VLDL.

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A Common Binding Site on the Microsomal Triglyceride Transfer Protein for Apolipoprotein B and Protein Disulfide Isomerase

Cited by 91 publications

References 23 publications

A Deficiency of Microsomal Triglyceride Transfer Protein Reduces Apolipoprotein B Secretion

A Deficiency of Microsomal Triglyceride Transfer Protein Reduces Apolipoprotein B Secretion

Molecular screening of the microsomal triglyceride transfer protein: association between polymorphisms and both abdominal obesity and plasma apolipoprotein B concentration

The Activity of Microsomal Triglyceride Transfer Protein Is Essential for Accumulation of Triglyceride within Microsomes in McA-RH7777 Cells

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