February 1, 1998Journal of Biological Chemistry127 citationsOpen Access

The Microsomal Triglyceride Transfer Protein Catalyzes the Post-translational Assembly of Apolipoprotein B-100 Very Low Density Lipoprotein in McA-RH7777 Cells

SRSabina RustaeusUniversity of Alberta PSPia StillemarkBristol-Myers Squibb (Germany)KLKarin LindbergBristol-Myers Squibb (Germany)

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Abstract

In cells in which the lipoprotein assembly process had been inactivated by brefeldin A (BFA), membrane-associated apoB-100 disappeared without forming lipoproteins or being secreted, indicating that it was degraded. Reactivation of the assembly process by chasing the cells in the absence of BFA, gave rise to a quantitative recovery of the membrane-associated apoB-100 in the very low density lipoprotein (VLDL) fraction in the medium. These results indicate that the membrane-associated apoB-100 can be converted to VLDL.A new method was developed by which the major amount (88%) of microsomal apoB-100 but not integral membrane proteins could be extracted. The major effect of this method was to increase the recovery of apoB-100 that banded in the LDL and HDL density regions, suggesting that the membrane-associated form of apoB-100 is partially lipidated. We also investigated the role of the microsomal triglyceride transfer protein (MTP) in the assembly of apoB-100 VLDL using a photoactivatable MTP inhibitor (BMS-192951). This compound strongly inhibited the assembly and secretion of apoB-100 VLDL when present during the translation of the protein. To investigate the importance of MTP during the later stages in the assembly process, the cells were preincubated with BFA (to reversibly inhibit the assembly of apoB-100 VLDL) and pulse-labeled (+BFA) and chased (+BFA) for 30 min to obtain full-length apoB-100 associated with the microsomal membrane. Inhibition of MTP after the 30-min chase blocked assembly of VLDL. This indicates that MTP is important for the conversion of full-length apoB-100 into VLDL. Results from experiments in which a second chase (−BFA) was introduced before the inactivation of MTP indicated that only early events in this conversion of full-length apoB-100 into VLDL were blocked by the MTP inhibitor. Together these results indicate that there is a MTP-dependent “window” in the VLDL assembly process that occurs after the completion of apoB-100 but before the major amount of lipids is added to the VLDL particle. Thus the assembly of apoB-100 VLDL from membrane-associated apoB-100 involves an early MTP-dependent phase and a late MTP-independent phase, during which the major amount of lipid is added. In cells in which the lipoprotein assembly process had been inactivated by brefeldin A (BFA), membrane-associated apoB-100 disappeared without forming lipoproteins or being secreted, indicating that it was degraded. Reactivation of the assembly process by chasing the cells in the absence of BFA, gave rise to a quantitative recovery of the membrane-associated apoB-100 in the very low density lipoprotein (VLDL) fraction in the medium. These results indicate that the membrane-associated apoB-100 can be converted to VLDL. A new method was developed by which the major amount (88%) of microsomal apoB-100 but not integral membrane proteins could be extracted. The major effect of this method was to increase the recovery of apoB-100 that banded in the LDL and HDL density regions, suggesting that the membrane-associated form of apoB-100 is partially lipidated. We also investigated the role of the microsomal triglyceride transfer protein (MTP) in the assembly of apoB-100 VLDL using a photoactivatable MTP inhibitor (BMS-192951). This compound strongly inhibited the assembly and secretion of apoB-100 VLDL when present during the translation of the protein. To investigate the importance of MTP during the later stages in the assembly process, the cells were preincubated with BFA (to reversibly inhibit the assembly of apoB-100 VLDL) and pulse-labeled (+BFA) and chased (+BFA) for 30 min to obtain full-length apoB-100 associated with the microsomal membrane. Inhibition of MTP after the 30-min chase blocked assembly of VLDL. This indicates that MTP is important for the conversion of full-length apoB-100 into VLDL. Results from experiments in which a second chase (−BFA) was introduced before the inactivation of MTP indicated that only early events in this conversion of full-length apoB-100 into VLDL were blocked by the MTP inhibitor. Together these results indicate that there is a MTP-dependent “window” in the VLDL assembly process that occurs after the completion of apoB-100 but before the major amount of lipids is added to the VLDL particle. Thus the assembly of apoB-100 VLDL from membrane-associated apoB-100 involves an early MTP-dependent phase and a late MTP-independent phase, during which the major amount of lipid is added. There exist two forms of apolipoprotein B (apoB), 1The abbreviations used are: apoB, apolipoprotein B; BFA, brefeldin A; CHX, cycloheximide; HDL, high density lipoproteins; LDL, low density lipoproteins; MTP, the microsomal triglyceride transfer protein; VLDL, very low density lipoproteins. apoB-100 and apoB-48 (1Kane J.P. Hardman D.A. Paulus H.E. Proc. Natl. Acad. Sci. U. S. A. 1980; 77: 2465-2469Google Scholar, 2Kane J.P. Annu. Rev. Physiol. 1983; 45: 637-650Google Scholar). In humans apoB-100 is expressed in the liver, while apoB-48 is synthesized in the intestine (3Glickman R.M. Rogers M. Glickman J.N. Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 5296-5300Google Scholar). In some animals, such as the rat, both proteins are expressed in the liver. When expressed in liver, both apoB-100 and apoB-48 assemble into VLDL particles (4Borén J. Rustaeus S. Olofsson S.-O. J. Biol. Chem. 1994; 269: 25879-25888Google Scholar, 5Sjöberg A. Oscarsson J. Borén J. Edén S. Olofsson S.-O. J. Lipid. Res. 1996; 37: 275-289Google Scholar). When expressed in the intestine, they both have the capacity to assemble into chylomicrons (6Farese R.V. Véniant M.M. Cham C.M. Flynn L.M. Pierotti V. Loring J.F. Traber M. Ruland S. Stokowski R.S. Huszar D. Young S.G. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 6393-6398Google Scholar). Lipoprotein assembly is a complex process that is not yet understood in all detail. The availability of the McA-RH7777 rat hepatoma cell line, which assembles bona fide VLDL (4Borén J. Rustaeus S. Olofsson S.-O. J. Biol. Chem. 1994; 269: 25879-25888Google Scholar), has facilitated studies of this process. In addition, we have recently demonstrated that brefeldin A (BFA) reversibly inhibits the assembly of all apoB-100 lipoproteins, in particular VLDL (7Rustaeus S. Lindberg K. Borén J. Olofsson S.-O. J. Biol. Chem. 1995; 270: 28879-28886Google Scholar). During BFA treatment, apoB-100 appeared in a non-VLDL form that pelleted with the microsomal membrane after sodium carbonate extraction of the lumenal content of the microsomes (7Rustaeus S. Lindberg K. Borén J. Olofsson S.-O. J. Biol. Chem. 1995; 270: 28879-28886Google Scholar). Since it was possible to remove the BFA and reactivate the assembly process, we were able to demonstrate that this membrane-associated form of apoB-100 can be a precursor to apoB-100 VLDL (7Rustaeus S. Lindberg K. Borén J. Olofsson S.-O. J. Biol. Chem. 1995; 270: 28879-28886Google Scholar). Thus it seems that, under certain conditions, the assembly of apoB-100 VLDL involves the following steps: 1) translation and association with the endoplasmic reticulum membrane and 2) conversion of the membrane-associated VLDL precursor into VLDL. The microsomal triglyceride transfer protein (MTP) catalyzes the transfer of triglycerides, cholesteryl esters, and phospholipids between phospholipid surfaces (8Atzel A. Wetterau J.R. Biochemistry. 1993; 32: 10444-10450Google Scholar, 9Jamil H. Dickson Jr., J.K. Chu C.H. Lago J.K. Wetterau J.R. J. Biol. Chem. 1995; 270: Scholar). that or MTP rise to the of an absence of lipoproteins in the J.R. A. M. D. K. C.M. D.A. Wetterau J.R. 1993; Scholar). Thus MTP is for the assembly and secretion of lipoproteins D.A. H. D. D. Wetterau J.R. Natl. Acad. Sci. U. S. A. 1994; Scholar, J. J. Biol. Chem. 1994; 269: Scholar). results indicate that MTP is important for the early events in the assembly of rat apoB-48 VLDL. MTP was not for the of the major amount of lipid during the later stages of the apoB-48 VLDL assembly D.A. H. Olofsson S.-O. Borén J. J. Biol. Chem. 1996; Scholar). the role of MTP in the early or late of apoB-100 assembly have been This the results of studies to the of apoB-100 after it with the microsomal membrane. The of VLDL from this of apoB-100 was by The role of MTP in this assembly process was using the photoactivatable inhibitor and were from was from and brefeldin A from sodium sodium sodium and were from to was from was from was from and without were from was from and protein were from was from used for the and were from for was from McA-RH7777 cells were as (4Borén J. Rustaeus S. Olofsson S.-O. J. Biol. Chem. 1994; 269: 25879-25888Google in sodium sodium and in The cells were a and The cells were pulse-labeled and chased as (4Borén J. Rustaeus S. Olofsson S.-O. J. Biol. Chem. 1994; 269: 25879-25888Google Scholar). A was in and added to the to a of of cells and the microsomal fraction was as K. Borén J. M. A. Olofsson S.-O. J. Biol. Chem. Scholar). The lumenal content of the was from the by the sodium carbonate method S. H. J. Biol. 93: Scholar), with some as (4Borén J. Rustaeus S. Olofsson S.-O. J. Biol. Chem. 1994; 269: 25879-25888Google Scholar, K. M. Borén J. Olofsson S.-O. J. Biol. Chem. 1986; Scholar). The microsomes were also with a of sodium and J. Biol. Scholar). The was in the high and The of was and for The not the during the The the for the extraction with sodium carbonate The following were and A photoactivatable MTP D.A. H. Olofsson S.-O. Borén J. J. Biol. Chem. 1996; Scholar), was used in these The inhibitor of not was in and added to the cell the were in the To the the cells were for min with using a a of The in the cell during this process was and to be The lipoproteins present in the microsomal or in the were by as (4Borén J. Rustaeus S. Olofsson S.-O. J. Biol. Chem. 1994; 269: 25879-25888Google Scholar). was from and as (4Borén J. Rustaeus S. Olofsson S.-O. J. Biol. Chem. 1994; 269: 25879-25888Google Scholar). in and of the in the proteins in the were as M. K. M. M. Borén J. Olofsson S.-O. J. Scholar). To we used the following the by the were a as by the The were blocked with in with for This was by a with the the of in with and The were with for min To the were with an in with a for min with by for min with the were with for as by the McA-RH7777 cells were with BFA for for 30 min in the of BFA, and chased in the of BFA for an 30 this the major amount of the apoB-100 was associated with the membrane of the microsomes was to carbonate while amount of apoB-100 VLDL could be in the sodium carbonate in the lumenal of these microsomes chase The of apoB-100 VLDL in the microsomal was by of from the microsomes by the of sodium and not This extraction the major amount of apoB-100 from the microsomes Together these results (7Rustaeus S. Lindberg K. Borén J. Olofsson S.-O. J. Biol. Chem. 1995; 270: 28879-28886Google that the VLDL assembly is blocked by BFA and that the major amount of apoB-100 is associated with the membrane of the The apoB-100 that was present in the carbonate of the microsomes banded during in with a density VLDL, with the amount present in the density of HDL J. Rustaeus S. M. M. A. Olofsson S.-O. 1993; chase We to these lipoproteins as apoB-100 in the apoB-100 lipoproteins were into the under the used in the in chase This was the cells were with the chase for min chase 2) in the of BFA in a in the amount of apoB-100 that was associated with the microsomal while apoB-100 VLDL was or results from the of as were after chase The amount of apoB-100 HDL in the microsomal the during this These results indicate that membrane-associated apoB-100 is for the BFA was and the chase for min in the of chase this all apoB-100 had disappeared from the microsomal membrane and could be as VLDL in the medium. This that the membrane-associated can assemble into VLDL, indicating a We also a in the amount of apoB-100 associated with apoB-100 HDL in the lumenal In with results D.A. H. Olofsson S.-O. Borén J. J. Biol. Chem. 1996; Scholar), we that of MTP before of the cells inhibited the assembly and secretion of lipoproteins. with the MTP in only of two of the apoB-100 VLDL In the we investigated the effect of MTP the of the VLDL assembly process. This was also to a possible during which MTP was important for this of the assembly process. In these we the cells with BFA for for 30 min and chased for 30 min these the VLDL assembly was and full-length apoB-100 was associated with the microsomal membrane We introduced an chase for or min in the absence of The MTP inhibitor was after the and a new chase for min was This chase was in the absence of BFA but in the of The was and by the of the of the MTP the cells were in the the after the to be that the VLDL assembly and secretion in cells are during the chase with and the of apoB-100 is converted to VLDL and 1) (7Rustaeus S. Lindberg K. Borén J. Olofsson S.-O. J. Biol. Chem. 1995; 270: 28879-28886Google Scholar). the chase of the secretion of apoB-100 VLDL from the cells in which the MTP inhibitor was was only of that in the cells This capacity of the MTP inhibitor to inhibit the assembly process was present after an chase of the secretion of apoB-100 VLDL under these conditions, of that in the cells an chase of 30 min the effect of the MTP inhibitor the assembly of VLDL 30-min Thus the secretion of apoB-100 VLDL with was after the chase of 30 min and after of and possible for the of of VLDL assembly by the MTP inhibitor after of 30 min and could be that all membrane-associated apoB-100 was converted into VLDL during this This VLDL could be during the following To investigate this we the following McA-RH7777 cells were preincubated in the of BFA for pulse-labeled for 30 min and chased for 30 min chase of 30 or min (−BFA) was and the lipoproteins present in the microsomal were by We also the membrane-associated apoB-100 The results demonstrated that lipoproteins could be from the microsomes with sodium carbonate after an chase of 30 min cell 30 apoB-100 was associated with the microsomal membrane 30 (7Rustaeus S. Lindberg K. Borén J. Olofsson S.-O. J. Biol. Chem. 1995; 270: 28879-28886Google Scholar), all of the membrane-associated of apoB-100 30 was converted into VLDL and into the during the chase in the absence of BFA and of the chase of we a of apoB-100 VLDL in the microsomal cell In with the from the 30-min all of the membrane-associated apoB-100 was converted into VLDL and into the during the chase demonstrated of the VLDL assembly by the MTP inhibitor was after of and This indicates that MTP is important a of apoB-100 lipoprotein To that translation was before the inhibitor was the cells were with as The cells were preincubated with BFA for pulse-labeled for 30 and chased for 30 min in the of the 30-min the cells were with CHX, and the MTP inhibitor was the cells were chased for min (−BFA) in the of and The cells not the MTP inhibitor but were in the the of and In with results (4Borén J. Rustaeus S. Olofsson S.-O. J. Biol. Chem. 1994; 269: 25879-25888Google Scholar), apoB-100 VLDL was and in the of the protein had been the the assembly and secretion of apoB-100 VLDL was inhibited by the MTP inhibitor. Thus the secretion of apoB-100 VLDL was only of that in the This indicates that the of the assembly process by the MTP inhibitor is not of These that MTP a role in a process in apoB-100 lipoprotein the of these results is that a amount of apoB-100 in association with the membrane after sodium carbonate This the that there is of or forms of which could to a The of apoB-100 that associated with the membrane is not To this it is to remove and all of the apoB-100 from the membrane fraction during the when the assembly process is MTP-dependent after the of and This was by of a new extraction method that is a of sodium carbonate and very of with is to as A of this new with the carbonate extraction is in The cells were for or pulse-labeled for 30 min by a chase of between 30 and were with carbonate or using the A is a of the apoB-100 with both a density B is a between the amount of apoB-100 in the membrane. with and carbonate gave a of apoB-100 from the membrane carbonate In extraction in a recovery of of the apoB-100 with only in association with the membrane. of the membrane a that there were only in the protein of the membrane after the two extraction The added during the extraction To the of the effect of the extraction the recovery of proteins associated with the microsomal we the recovery of the integral membrane protein by In these the membrane was after extraction by the two in and to the of the we that extraction with gave rise to a recovery of in the membrane as the carbonate extraction Together the results in that extraction of microsomes with a of low of and to a very in the of apoB-100 from the but not integral membrane proteins extraction with carbonate of the by a increase of apoB-100 in all density in to extraction with carbonate there was an of particles in the LDL and HDL density To the microsomes were with carbonate and with The results that the of and the of extraction of apoB-100 present in the HDL and LDL density extraction of a recovery of the of apoB-100 forms associated with the microsomal particular with is that it the of the lipoprotein In particular it the of VLDL. To this we the after a of the cells only VLDL to with carbonate or The were to and apoB-100 was from fraction by and by and The results demonstrated that the VLDL during both extraction of particles was of the of apoB-100 between the density is as for in VLDL, in LDL, and in the HDL density for in VLDL, in LDL, and in the HDL density Thus the recovery of apoB-100 in VLDL after carbonate was not not the recovery of apoB-100 VLDL with The method was used to apoB-100 from the microsomes of cells that had been preincubated with BFA for pulse-labeled for 30 min chased for 30 min and chased for or 30 min without A that the membrane was of of the by demonstrated that the major amount of apoB-100 was present in the HDL density A amount of apoB-100 was present in the VLDL or density the amount of VLDL or density particles not between the when the assembly was MTP and and when the assembly was MTP of 30 min or In we a amount of apoB-100 the HDL density after the chase after the 30-min Together this of strongly the that the effect of the 30-min chase was to all apoB-100 into lumenal VLDL or that VLDL particles were associated with the membrane. the of apoB-100 VLDL in the during the chase following the 30-min chase could be only by assembly from a non-VLDL form of apoB-100 associated with the microsomal membrane A and the results in indicate that MTP a role in the process of membrane-associated apoB-100 to VLDL. results indicate that this of MTP the assembly process occurs before the major amount of lipid is added and the VLDL is The that it a chase in the absence of BFA to reactivate the process that the major amount of lipids and VLDL particles into the of the with results (7Rustaeus S. Lindberg K. Borén J. Olofsson S.-O. J. Biol. Chem. 1995; 270: 28879-28886Google Scholar). from the cells indicated that MTP is of importance for VLDL assembly after the completion of apoB-100 and that this MTP could be by a These experiments the to reversibly inhibit VLDL assembly by To that the MTP effect was also to cells not with BFA, we the following The cells were pulse-labeled for 30 min and with to We introduced a chase for or 30 min These were by MTP for a the cells were with only and without the inhibitor. the cells were chased for min in the of and the secretion of apoB-100 VLDL was The results indicate that there was a of VLDL assembly when MTP was introduced after the chase of min of VLDL in the was of that for the This the that MTP the assembly of apoB-100 VLDL after translation is an chase of min in the of CHX, the recovery (to of the after an chase of 30 min 30 the recovery was which is in the of that after the chase in cells with BFA The amount of apoB-100 was present in the cells after the with the MTP inhibitor before the under the These results the that MTP the apoB-100 VLDL assembly and that there is a during which the process is results from J. M. A. Olofsson S.-O. J. Biol. Chem. Scholar), as as from J. S. Proc. Natl. Acad. Sci. U. S. A. Scholar), have indicated that membrane-associated apoB-100 is to we results which indicated that this form of apoB-100 can also be a precursor to VLDL (7Rustaeus S. Lindberg K. Borén J. Olofsson S.-O. J. Biol. Chem. 1995; 270: 28879-28886Google Scholar). In these experiments we used BFA to reversibly the assembly of lipoproteins, in particular VLDL. was demonstrated that BFA the association of with the endoplasmic reticulum membrane. When the BFA was the cells assembly of apoB-100 VLDL. In this we used the but to the of the membrane-associated apoB-100 during a chase in the of BFA, under that inhibited the VLDL assembly process. The results a in the amount of membrane-associated Since apoB-100 lipoproteins were or secreted, these results indicate that the membrane-associated apoB-100 was by the BFA before the apoB-100 was in of apoB-100 VLDL, which was in the medium. These results demonstrate that the membrane-associated apoB-100 is a precursor to VLDL. when the assembly process is this be in the In with results J. Rustaeus S. M. M. A. Olofsson S.-O. 1993; Scholar), the present indicate that the assembly process a role in the of apoB-100 that is not to the assembly process be The of the membrane-associated apoB-100 is In this we demonstrate that the microsomal could be of apoB-100 by extraction with sodium carbonate with of and The of are the and have been to remove lumenal proteins and membrane proteins but not integral membrane proteins J. Biol. Scholar). In an we that the extraction not recovery of membrane proteins from the membrane during the extraction with sodium carbonate was that, a increase in the recovery of apoB-100 in all density was we that the major effect of and high was to apoB-100 that banded in the HDL and LDL density We have demonstrated the of such forms of apoB-100 lipoproteins in sodium carbonate of the and we have that the form that in the HDL density be a precursor to lipoproteins K. Borén J. M. A. Olofsson S.-O. J. Biol. Chem. Scholar). a precursor role for apoB-100 HDL is by the results of the present is that apoB-100 HDL a of the membrane-associated that is during extraction with carbonate that the membrane-associated form of apoB-100 and the particles to the of This in both the membrane-associated form of apoB-100 the and apoB-100 HDL the particles by sodium to be for apoB-100 VLDL studies have demonstrated that MTP is for the assembly of lipoproteins D.A. H. D. D. Wetterau J.R. Natl. Acad. Sci. U. S. A. 1994; Scholar, J. J. Biol. Chem. 1994; 269: Scholar). it has been that in the MTP rise to the of J.R. A. M. Scholar, D. K. C.M. D.A. Wetterau J.R. 1993; Scholar). the that MTP is in is the of the role of this protein in the assembly of the with has been demonstrated M. Wetterau J. J. Biol. Chem. 1996; Scholar, J. Biol. Chem. 1996; and to the of apoB, which is for the of MTP A. Wetterau J.R. J. Biol. Chem. 1996; Scholar, J. Res. 1996; 37: Scholar). In a we demonstrated that MTP is for the early events in the assembly of apoB-48 VLDL in the McA-RH7777 but not to be for the in which the major amount of lipids was added to the D.A. H. Olofsson S.-O. Borén J. J. Biol. Chem. 1996; Scholar). In addition, it has recently been that of MTP to min after a of blocked the secretion of apoB-100 from cells J. 1996; Scholar). this the MTP inhibitor and secretion was This that, as in the of MTP also a role in the early stages of apoB-100 lipoprotein but not in the later with the cells is that they not assemble amount of bona fide VLDL J. Rustaeus S. M. M. A. Olofsson S.-O. 1993; Scholar), but an in The assembly of this occurs to a J. M. J. A. Olofsson S.-O. J. Biol. Chem. Scholar). a precursor to apoB-100 VLDL to be a membrane-associated form of full-length apoB-100 (7Rustaeus S. Lindberg K. Borén J. Olofsson S.-O. J. Biol. Chem. 1995; 270: 28879-28886Google Scholar). We that a photoactivatable MTP inhibitor could the assembly and secretion of apoB-100 VLDL not only when the inhibitor was to the of the but also when the was after completion of the membrane-associated apoB-100 VLDL This indicates that MTP in the conversion of membrane-associated apoB-100 to VLDL. results also indicate that there is a “window” which this process is This occurs in cells after translation is but before they have capacity to assemble and VLDL particles into the after BFA is This in indicates that MTP is not in the of the major amount of lipid to the but in the of apoB-100 for this process. This with that the of the major amount of lipid to apoB-48 VLDL occurs in an MTP-independent D.A. H. Olofsson S.-O. Borén J. J. Biol. Chem. 1996; Scholar). The of the during which the assembly process was MTP-dependent was To that this was not to an introduced by the BFA treatment, an was In this we used to the the results were a during which apoB-100 lipoprotein assembly was the to to assemble and apoB-100 VLDL (4Borén J. Rustaeus S. Olofsson S.-O. J. Biol. Chem. 1994; 269: 25879-25888Google Scholar), the of MTP be results indicate that MTP is of importance for the of a that full-length membrane-associated apoB-100 to be into VLDL and This that an important of MTP is to apoB-100 for the assembly with the major amount of The of this is a that to be in possible can be The that of MTP lipid transfer has such a effect the assembly process during translation of that MTP is for the protein during or after by the of the protein. has been that of in particular of that into J.P. 1994; Scholar). The that are for apoB, are to the between and the lipoprotein J.P. 1994; Scholar). could be that these lipid transfer to to form a of the of the In the absence of MTP, these to the of the The that MTP is also after the completion of apoB-100 could that of the protein after the translation of the protein. There is a that of apoB-100 is to the lumenal of the membrane J. Rustaeus S. M. M. A. Olofsson S.-O. 1993; Scholar, J. Biol. Chem. Scholar, C.M. D. J. Biol. Scholar). MTP in such a by this of the protein to as it the of the endoplasmic In this the protein a that it to with the VLDL assembly process. be in that the association between apoB-100 and the microsomal membrane is not results have appeared in the the of apoB-100 the of the endoplasmic reticulum membrane K. M. Borén J. Olofsson S.-O. J. Biol. Chem. 1986; Scholar, J. Rustaeus S. M. M. A. Olofsson S.-O. 1993; J. Biol. Chem. Scholar, C.M. D. J. Biol. Scholar, J. Biol. Chem. 1994; 269: Scholar, J. Scholar). is that apoB-100 is and that the of the occurs proteins in to The that the membrane-associated precursor could be under that have been not to integral membrane proteins J. Biol. in this the that apoB-100 is associated with the membrane is an integral protein. This not a by or membrane be that the has recently been demonstrated to not only in the of proteins to the endoplasmic reticulum but also in the of lumenal protein for by for and Biol. for a and Together a for the assembly of apoB-100 VLDL. to this apoB-100 is and partially into a membrane-associated VLDL precursor This process is The assembly of VLDL from this precursor occurs in an MTP-dependent during which an VLDL precursor is The is MTP-independent and the major amount of lipids to be the protein. We for

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