Key points are not available for this paper at this time.
Apolipoprotein B (apoB) is required for the hepatic assembly and secretion of very low density lipoprotein (VLDL). The LDL receptor (LDLR) promotes post-translational degradation of apoB and thereby reduces VLDL particle secretion. We investigated the trafficking pathways and ligand requirements for the LDLR to promote degradation of apoB. We first tested whether the LDLR drives apoB degradation in an endoplasmic reticulum (ER)-associated pathway. Primary mouse hepatocytes harboring an ethyl-nitrosourea-induced, ER-retained mutant LDLR secreted comparable levels of apoB with LDLR-null hepatocytes, despite reduced secretion from cells expressing the wild-type LDLR. Additionally, treatment of cells with brefeldin A inhibited LDLR-dependent degradation. However, this rescue was reversible, and degradation of apoB occurred upon removal of brefeldin A. To characterize the lipoprotein reuptake pathway of degradation, we employed an LDLR mutant defective in constitutive endocytosis and internalization of apoB. This mutant was as effective in reducing apoB secretion as the wild-type LDLR. However, the effect was dependent on apolipoprotein E (apoE) as only the wild-type LDLR, and not the endocytic mutant, reduced apoB secretion in apoE-null cells. Treatment with heparin rescued a pool of apoB in cells expressing the endocytic mutant, indicating that reuptake of VLDL via apoE still occurs with this mutant. Finally, an LDLR mutant defective in binding apoB but not apoE reduced apoB secretion in an apoE-dependent manner. Together, these data suggest that the LDLR directs apoB to degradation in a post-ER compartment. Furthermore, the reuptake mechanism of degradation occurs via internalization of apoB through a constitutive endocytic pathway and apoE through a ligand-dependent pathway. Apolipoprotein B (apoB) is required for the hepatic assembly and secretion of very low density lipoprotein (VLDL). The LDL receptor (LDLR) promotes post-translational degradation of apoB and thereby reduces VLDL particle secretion. We investigated the trafficking pathways and ligand requirements for the LDLR to promote degradation of apoB. We first tested whether the LDLR drives apoB degradation in an endoplasmic reticulum (ER)-associated pathway. Primary mouse hepatocytes harboring an ethyl-nitrosourea-induced, ER-retained mutant LDLR secreted comparable levels of apoB with LDLR-null hepatocytes, despite reduced secretion from cells expressing the wild-type LDLR. Additionally, treatment of cells with brefeldin A inhibited LDLR-dependent degradation. However, this rescue was reversible, and degradation of apoB occurred upon removal of brefeldin A. To characterize the lipoprotein reuptake pathway of degradation, we employed an LDLR mutant defective in constitutive endocytosis and internalization of apoB. This mutant was as effective in reducing apoB secretion as the wild-type LDLR. However, the effect was dependent on apolipoprotein E (apoE) as only the wild-type LDLR, and not the endocytic mutant, reduced apoB secretion in apoE-null cells. Treatment with heparin rescued a pool of apoB in cells expressing the endocytic mutant, indicating that reuptake of VLDL via apoE still occurs with this mutant. Finally, an LDLR mutant defective in binding apoB but not apoE reduced apoB secretion in an apoE-dependent manner. Together, these data suggest that the LDLR directs apoB to degradation in a post-ER compartment. Furthermore, the reuptake mechanism of degradation occurs via internalization of apoB through a constitutive endocytic pathway and apoE through a ligand-dependent pathway. Apolipoprotein B (apoB) 3The abbreviations used are: apoB, apolipoprotein B; apoE, apolipoprotein E; ARH, autosomal hypercholesterolemia; LDL, low density lipoprotein; VLDL, very low density lipoprotein; LDLR, LDL receptor; ER, endoplasmic reticulum; β-Gal, β-galactosidase; BFA, brefeldin A; FH, familial hypercholesterolemia; LSD, least significant difference; WT, wild type; DMEM, Dulbecco's modified Eagle's medium; Ad, adenoviral; pfu, plaque-forming unit. is the major protein component of very low density lipoprotein (VLDL), the triglyceride-enriched lipoprotein particle produced by the liver. apoB is essential for the assembly and secretion of nascent VLDL particles (1Davis R.A. Biochim. Biophys. Acta. 1999; 1440: 1-31Crossref PubMed Scopus (164) Google Scholar, 2Fisher E.A. Ginsberg H.N. J. Biol. Chem. 2002; 277: 17377-17380Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar, 3Blasiole D.A. Davis R.A. Attie A.D. Mol. Biosyst. 2007; 3: 608-619Crossref PubMed Scopus (90) Google Scholar). apoB is constitutively expressed, and its stability is regulated through co- and post-translational degradation (4Borchardt R.A. Davis R.A. J. Biol. Chem. 1987; 262: 16394-16402Abstract Full Text PDF PubMed Google Scholar). Therefore, the number of VLDL particles secreted is a function of the proportion of apoB that escapes degradation. The LDL receptor (LDLR) is a ubiquitously expressed protein responsible for the clearance of cholesterol-rich lipoproteins from the bloodstream through its ligands, apoB and apolipoprotein E (apoE). A loss in LDLR activity, as occurs in humans with familial hypercholesterolemia (FH), results in a defect in LDL clearance (5Brown M.S. Goldstein J.L. Science. 1986; 232: 34-47Crossref PubMed Scopus (4383) Google Scholar). In addition to its role in mediating lipoprotein clearance, the LDLR also regulates VLDL secretion. Studies in humans (6James R.W. Martin B. Pometta D. Fruchart J.C. Duriez P. Puchois P. Farriaux J.P. Tacquet A. Demant T. Clegg R.J. Munro A. Oliver M.F. Packard C.J. Shepherd J. J. Lipid Res. 1989; 30: 159-169Abstract Full Text PDF PubMed Google Scholar, 7Tremblay A.J. Lamarche B. Ruel I.L. Hogue J.C. Bergeron J. Gagne C. Couture P. J. Lipid Res. 2004; 45: 866-872Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 8Millar J.S. Maugeais C. Ikewaki K. Kolansky D.M. Barrett P.H. Budreck E.C. Boston R.C. Tada N. Mochizuki S. Defesche J.C. Wilson J.M. Rader D.J. Arterioscler. Thromb. Vasc. Biol. 2005; 25: 560-565Crossref PubMed Scopus (76) Google Scholar), mice (9Horton J.D. Shimano H. Hamilton R.L. Brown M.S. Goldstein J.L. J. Clin. Investig. 1999; 103: 1067-1076Crossref PubMed Scopus (158) Google Scholar, 10Nassir F. Xie Y. Patterson B.W. Luo J. Davidson N.O. J. Lipid Res. 2004; 45: 1649-1659Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 11Teusink B. Mensenkamp A.R. van der Boom H. Kuipers F. van Dijk K.W. Havekes L.M. J. Biol. Chem. 2001; 276: 40693-40697Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar), primary hepatocytes (12Twisk J. Gillian-Daniel D.L. Tebon A. Wang L. Barrett P.H. Attie A.D. J. Clin. Investig. 2000; 105: 521-532Crossref PubMed Google Scholar, 13Gillian-Daniel D.L. Bates P.W. Tebon A. Attie A.D. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 4337-4342Crossref PubMed Scopus (61) Google Scholar, 14Larsson S.L. Skogsberg J. Bjorkegren J. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, S. C. K. A. A.R. 2001; PubMed Scopus Google Scholar), and cells R.W. E.A. J. Biol. Chem. Full Text PDF PubMed Google that the loss of LDLR to secretion of VLDL to a in the degradation of apoB. The particles secreted from LDLR (6James R.W. Martin B. Pometta D. Fruchart J.C. Duriez P. Puchois P. Farriaux J.P. Tacquet A. Demant T. Clegg R.J. Munro A. Oliver M.F. Packard C.J. Shepherd J. J. Lipid Res. 1989; 30: 159-169Abstract Full Text PDF PubMed Google Scholar, 10Nassir F. Xie Y. Patterson B.W. Luo J. Davidson N.O. J. Lipid Res. 2004; 45: 1649-1659Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 14Larsson S.L. Skogsberg J. Bjorkegren J. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google and (6James R.W. Martin B. Pometta D. Fruchart J.C. Duriez P. Puchois P. Farriaux J.P. Tacquet A. Demant T. Clegg R.J. Munro A. Oliver M.F. Packard C.J. Shepherd J. J. Lipid Res. 1989; 30: 159-169Abstract Full Text PDF PubMed Google Scholar, 11Teusink B. Mensenkamp A.R. van der Boom H. Kuipers F. van Dijk K.W. Havekes L.M. J. Biol. Chem. 2001; 276: 40693-40697Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar), that the LDLR particles for degradation. that the LDLR through reuptake of nascent VLDL particles (12Twisk J. Gillian-Daniel D.L. Tebon A. Wang L. Barrett P.H. Attie A.D. J. Clin. Investig. 2000; 105: 521-532Crossref PubMed Google Scholar, R.W. E.A. J. Biol. Chem. Full Text PDF PubMed Google in a to the internalization of LDL, as as through a of nascent VLDL particles to degradation (12Twisk J. Gillian-Daniel D.L. Tebon A. Wang L. Barrett P.H. Attie A.D. J. Clin. Investig. 2000; 105: 521-532Crossref PubMed Google Scholar, S. C. K. A. A.R. 2001; PubMed Scopus Google Scholar). In the we we whether the LDLR on apoB in the a post-ER in the pathway. we the ligand requirements for reuptake of VLDL We that LDLR-dependent apoB degradation occurs from the and that of the LDLR on the VLDL apoB and We also that an LDLR mutant defective in constitutive endocytosis is still of mediating the reuptake of VLDL via a endocytic mechanism C. P. N. J.C. J. J. Clin. Investig. 2007; PubMed Scopus Google Scholar, P. J.C. J. 2007; PubMed Scopus Google Scholar). This on of degradation of apoB and pathways by an LDLR mutant VLDL secretion. and and mice from the and in of and and on a and of for by as B. Mensenkamp A.R. van der Boom H. Kuipers F. van Dijk K.W. Havekes L.M. J. Biol. Chem. 2001; 276: 40693-40697Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). cells in low with and a density of on in cells a density of in not with used of by the was from S. U. H. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google from with and and was the of A with of the was from H. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google by with and and the of was from with and and the and of of the LDLR by of the wild-type LDLR (12Twisk J. Gillian-Daniel D.L. Tebon A. Wang L. Barrett P.H. Attie A.D. J. Clin. Investig. 2000; 105: 521-532Crossref PubMed Google in the The LDLR from with and and the of of the The the and the the and of by to hepatocytes in and in the the for cells in with and the with the and and as (12Twisk J. Gillian-Daniel D.L. Tebon A. Wang L. Barrett P.H. Attie A.D. J. Clin. Investig. 2000; 105: 521-532Crossref PubMed Google that to and with a The was with a LDLR the first of the D.J. S.L. Attie A.D. PubMed Scopus Google Scholar). To protein by hepatocytes and as N. D.A. Tebon A. S. J. Attie A.D. A. 2007; PubMed Scopus Google Scholar). The and used A and internalization cells with on for The cells with and with with and for cells with and to the was with a with and with for in and cells in with for cells and cells with for with with and and for the in the A was in and to the a of was in and to the a of and for apoB and from and as (12Twisk J. Gillian-Daniel D.L. Tebon A. Wang L. Barrett P.H. Attie A.D. J. Clin. Investig. 2000; 105: 521-532Crossref PubMed Google Scholar). used for apoB and LDL (12Twisk J. Gillian-Daniel D.L. Tebon A. Wang L. Barrett P.H. Attie A.D. J. Clin. Investig. 2000; 105: 521-532Crossref PubMed Google and by by with a by with a and with In apoB by to for in and of In of expressed by protein R.J. J. Biol. Chem. Full Text PDF PubMed Google Scholar). The data expressed in and the was to treatment of by of least significant to treatment The LDLR apoB through a that of ER-retained LDLR reduced apoB secretion to the as expressing the LDLR D.L. Bates P.W. Tebon A. Attie A.D. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 4337-4342Crossref PubMed Scopus (61) Google Scholar). This that the LDLR directs apoB to degradation through an pathway. To this in a we used a mouse from an with B. J. 2007; PubMed Scopus Google Scholar). The hypercholesterolemia in this mouse results from a in the to a the To whether the mouse LDLR we for the LDLR with from primary hepatocytes from WT, mutant, and The LDLR is of the the mutant is of the of the of the LDLR occurs from the ER, in the S. H. Brown M.S. Goldstein J.L. J. Biol. Chem. Full Text PDF PubMed Google Scholar). Therefore, the of the mutant LDLR that is in the To we the LDLR and its with The LDLR in the cells in the but also in the of the not with the A In the mutant a with the To whether the ER-retained LDLR mutant reduces apoB we the secreted protein levels from primary hepatocytes from WT, and from WT, but not the secreted and hepatocytes the ER-retained LDLR was to apoB this that the LDLR-dependent of apoB secretion of the LDLR from the To whether of the LDLR and apoB in the degradation of apoB, we investigated the effect of on LDLR-dependent apoB degradation. is a that of from the J. J.S. 1989; Full Text PDF PubMed Scopus Google Scholar). not the degradation of apoB in T. A. T. J. Biol. Chem. Full Text PDF PubMed Google Scholar, N. H. Ginsberg H.N. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We employed expressing of in a manner. This for a low of LDLR in by the of the to the and To a of LDLR with this in the of BFA, we mouse hepatocytes with to the wild-type LDLR in We the cells for and with for The of the LDLR in a in and and a a in indicating that degradation of apoB occurred in the of the LDLR. To the effect of BFA, we the cells in the of for and for an in the of to the Treatment with levels of and indicating that from the the levels of apoB not the and cells with However, removal of the an LDLR-dependent in and and results a of an LDLR-dependent effect on apoB in the and suggest that from the is required for apoB degradation. LDLR in apoB as as the investigated of apoB degradation of reuptake through endocytosis (12Twisk J. Gillian-Daniel D.L. Tebon A. Wang L. Barrett P.H. Attie A.D. J. Clin. Investig. 2000; 105: 521-532Crossref PubMed Google Scholar, R.W. E.A. J. Biol. Chem. Full Text PDF PubMed Google Scholar). We employed an LDLR mutant, the LDLR Brown M.S. Goldstein J.L. 1986; 45: Full Text PDF PubMed Scopus Google Scholar), a of for the in the in the This is required for the constitutive endocytic responsible for internalization and degradation of lipoproteins in cells Brown M.S. Goldstein J.L. 1986; 45: Full Text PDF PubMed Scopus Google Scholar, M.S. Goldstein J.L. Full Text PDF PubMed Scopus Google Scholar). To that the LDLR is also defective in endocytosis in primary we expressed the and LDLR with in hepatocytes and the LDLR to its with the mouse LDLR the expressed LDLR in the and the of the In the LDLR was the and To a of the endocytic of the LDLR, hepatocytes expressing the LDLR with a on to for binding the The cells to for to for internalization of the expressing the and LDLR the of the the to However, only cells expressing the LDLR significant internalization of the from the results with the data that the LDLR is defective in constitutive endocytosis in primary We that the LDLR least defective in apoB secretion to its defect in To this we the secretion of apoB hepatocytes expressing levels of LDLR, LDLR, and the and the LDLR in secretion levels of LDLR of the to comparable in secretion. To that the LDLR is in degradation of apoB, we a with the LDLR A and cells expressing the LDLR a in the of and data that despite the defect in constitutive endocytic activity, the LDLR is effective in apoB secretion. apoE the LDLR-dependent in apoB of the LDLR to apoB secretion that the is of However, data is an that to the LDLR the to its endocytosis S. P. J.C. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, L.M. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: PubMed Scopus Google Scholar, C. J.C. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The in the LDLR this S. P. J.C. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar), for its loss in constitutive endocytic in However, that despite a defect in the internalization of hepatocytes and LDLR the to apoE C. P. N. J.C. J. J. Clin. Investig. 2007; PubMed Scopus Google Scholar, P. J.C. J. 2007; PubMed Scopus Google Scholar). We that the LDLR apoB secretion through reuptake of VLDL via To this we the secretion of apoB from hepatocytes expressing the LDLR. with However, of the LDLR secretion that least a of apoB degradation occurs through a with the LDLR. of the LDLR was in reducing secretion data that the of the LDLR to apoB secretion from hepatocytes with an apoE results from binding to apoE on the VLDL The that apoE is the ligand responsible for the of the LDLR to apoB secretion. To whether this occurs through lipoprotein as we tested the effect of heparin on the of the LDLR to apoB secretion. apoB and apoE in the and with the LDLR J.L. Brown M.S. Full Text PDF PubMed Scopus Google Scholar). heparin LDLR the (12Twisk J. Gillian-Daniel D.L. Tebon A. Wang L. Barrett P.H. Attie A.D. J. Clin. Investig. 2000; 105: 521-532Crossref PubMed Google Scholar). Treatment with heparin effect in cells but rescued a pool of apoB in cells This that the LDLR is of apoB secretion through internalization of To whether the apoE-dependent internalization of apoB with the LDLR occurs with endocytic trafficking results from a loss in the constitutive endocytic we employed an LDLR mutant that is defective in binding apoB but and apoE Brown M.S. Goldstein J.L. J. Biol. Chem. 1989; Full Text PDF PubMed Google Scholar). of this reduced apoB secretion in wild-type hepatocytes but to in hepatocytes This that the internalization of apoE occurs endocytic trafficking and is not a of a defect in the constitutive endocytic pathway. In this we by the LDLR regulates the secretion of We investigated of LDLR in the ER, the nascent VLDL particle is and the VLDL particle reuptake We that the LDLR not the degradation of apoB the and that from the is required for LDLR In of the ER, we that the LDLR apoB secretion through reuptake of nascent VLDL and that apoB and apoE in this and In we that the LDLR regulates apoB secretion through a endocytic mechanism via internalization of apoE of the post-translational apoB degradation that VLDL secretion occurs in the the of VLDL assembly (1Davis R.A. Biochim. Biophys. Acta. 1999; 1440: 1-31Crossref PubMed Scopus (164) Google Scholar, 2Fisher E.A. Ginsberg H.N. J. Biol. Chem. 2002; 277: 17377-17380Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar). that of ER-retained LDLR apoB degradation D.L. Bates P.W. Tebon A. Attie A.D. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 4337-4342Crossref PubMed Scopus (61) Google Scholar), that the LDLR was this In the we of a mouse mutant with an in the LDLR that results in its in the with this hypercholesterolemia and and and an humans with (5Brown M.S. Goldstein J.L. Science. 1986; 232: 34-47Crossref PubMed Scopus (4383) Google Scholar). This mouse a to the of an LDLR in the on apoB secretion. In to the expressed, ER-retained LDLR mutant to apoB secretion Additionally, the of apoB and LDLR from the with the of the LDLR to apoB degradation Together, these results suggest that the LDLR VLDL secretion in post-ER This is by the that very of the pool of the LDLR the is with the LDLR its in post-ER that LDLR-dependent degradation occurs of assembly and of the VLDL that the LDLR secretion of particles (6James R.W. Martin B. Pometta D. Fruchart J.C. Duriez P. Puchois P. Farriaux J.P. Tacquet A. Demant T. Clegg R.J. Munro A. Oliver M.F. Packard C.J. Shepherd J. J. Lipid Res. 1989; 30: 159-169Abstract Full Text PDF PubMed Google Scholar, 10Nassir F. Xie Y. Patterson B.W. Luo J. Davidson N.O. J. Lipid Res. 2004; 45: 1649-1659Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 11Teusink B. Mensenkamp A.R. van der Boom H. Kuipers F. van Dijk K.W. Havekes L.M. J. Biol. Chem. 2001; 276: 40693-40697Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 14Larsson S.L. Skogsberg J. Bjorkegren J. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). The LDLR function as a to the secretion of We that the and data the ER-retained in the of the LDLR. The in the by the in an manner. We that the of the ER-retained degradation of apoB in a not the employed in this for low levels in and with of suggest that the in apoB secretion in this that with the LDLR, not from of the LDLR not degradation of apoB in the apoB to from the of the LDLR to apoB secretion in hepatocytes to the LDLR from a in the LDLR its the of the LDLR to apoB secretion through reuptake of apoE data a endocytic mechanism employed by the LDLR. upon ligand binding K. J.M. J. Sci. 3: Google Scholar), the LDLR was to constitutive endocytosis Brown M.S. U. Goldstein J.L. J. Biol. PubMed Scopus Google Scholar, Goldstein J.L. Brown M.S. Full Text PDF PubMed Scopus Google Scholar, J.L. Brown M.S. Biol. PubMed Scopus Google Scholar). However, that endocytosis of the LDLR, a constitutive pathway by binding of the ARH, to the and an pathway C. P. N. J.C. J. J. Clin. Investig. 2007; PubMed Scopus Google Scholar, P. J.C. J. 2007; PubMed Scopus Google Scholar). binding of apoE, but not apoB, the pathway. of through loss of through the in the LDLR mutant, a defect in constitutive endocytosis and internalization of apoB Brown M.S. Goldstein J.L. 1986; 45: Full Text PDF PubMed Scopus Google Scholar, M.S. Goldstein J.L. Full Text PDF PubMed Scopus Google Scholar, C. J.C. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). This results in hypercholesterolemia in humans M.S. Goldstein J.L. Full Text PDF PubMed Scopus Google and mice C. J.C. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), to a defect in LDL However, a loss of the pathway still for the internalization of as VLDL C. P. N. J.C. J. J. Clin. Investig. 2007; PubMed Scopus Google Scholar, P. J.C. J. 2007; PubMed Scopus Google Scholar). The these the of the LDLR to apoB secretion through reuptake was dependent on the of apoE and that the LDLR through the ligand-dependent endocytic pathway. This a function of this pathway. In that the of VLDL, as occurs with with of (6James R.W. Martin B. Pometta D. Fruchart J.C. Duriez P. Puchois P. Farriaux J.P. Tacquet A. Demant T. Clegg R.J. Munro A. Oliver M.F. Packard C.J. Shepherd J. J. Lipid Res. 1989; 30: 159-169Abstract Full Text PDF PubMed Google Scholar, 7Tremblay A.J. Lamarche B. Ruel I.L. Hogue J.C. Bergeron J. Gagne C. Couture P. J. Lipid Res. 2004; 45: 866-872Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 8Millar J.S. Maugeais C. Ikewaki K. Kolansky D.M. Barrett P.H. Budreck E.C. Boston R.C. Tada N. Mochizuki S. Defesche J.C. Wilson J.M. Rader D.J. Arterioscler. Thromb. Vasc. Biol. 2005; 25: 560-565Crossref PubMed Scopus (76) Google Scholar), not in with the and This is the first to apoE as a ligand that the effect of the LDLR on apoB secretion. an LDLR-dependent of secretion in addition to secretion (12Twisk J. Gillian-Daniel D.L. Tebon A. Wang L. Barrett P.H. Attie A.D. J. Clin. 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Biol. 2001; PubMed Scopus Google Scholar, C. K. J.M. Rader D.J. J. Lipid Res. 2000; Full Text Full Text PDF PubMed Google Scholar), a that is of the LDLR B. Mensenkamp A.R. van der Boom H. Kuipers F. van Dijk K.W. Havekes L.M. J. Biol. Chem. 2001; 276: 40693-40697Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). this that apoE is required for a in VLDL secretion in a that is dependent on the LDLR. The is by the that of apoE to the lipoprotein assembly the A.R. B. C.J. Havekes L.M. Kuipers F. J. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar), LDLR occurs from the This that apoE in but to in the assembly and secretion of mice VLDL wild-type mice C. K. J.M. Rader D.J. J. Lipid Res. 2000; Full Text Full Text PDF PubMed Google Scholar, F. Y. H. R.J. Havekes L.M. J. Clin. Investig. PubMed Scopus Google Scholar), its role in lipoprotein assembly to of its in the of of the in this a of VLDL secretion in J.S. Maugeais C. Ikewaki K. Kolansky D.M. Barrett P.H. Budreck E.C. Boston R.C. Tada N. Mochizuki S. Defesche J.C. Wilson J.M. Rader D.J. Arterioscler. Thromb. Vasc. Biol. 2005; 25: 560-565Crossref PubMed Scopus (76) Google Scholar). A with a of LDLR and only a an in VLDL secretion in the However, removal of a of the from the a significant in VLDL secretion in the the from the a mutant that is defective in binding apoB but still apoE and a mutant that the but not internalization in the ER-retained a data a of LDLR in the as as the internalization of apoE in the of apoB secretion by the LDLR. In addition to the reuptake pathway in this of that the LDLR also through an mechanism (12Twisk J. Gillian-Daniel D.L. Tebon A. Wang L. Barrett P.H. Attie A.D. J. Clin. Investig. 2000; 105: 521-532Crossref PubMed Google Scholar, 14Larsson S.L. Skogsberg J. Bjorkegren J. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, S. C. K. A. A.R. 2001; PubMed Scopus Google Scholar). of the of apoB secretion that of LDLR occurs through a reuptake mechanism and occurs through an mechanism (12Twisk J. Gillian-Daniel D.L. Tebon A. Wang L. Barrett P.H. Attie A.D. J. Clin. Investig. 2000; 105: 521-532Crossref PubMed Google Scholar). We that the LDLR in a to the The receptor in the and the to to 2004; Scopus Google Scholar). is that the LDLR nascent VLDL from the pathway to the endocytic pathway in the manner. of suggest that a for the LDLR. is a protein that to the LDLR and its degradation in S. D. J. L. J. D. Tebon A. Attie A.D. Rader D.J. C. L. A. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, J.D. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, E.A. J.L. Proc. Natl. Acad. Sci. U. S. A. 2005; PubMed Scopus Google Scholar). The addition of in is for degradation of the LDLR in wild-type but not hepatocytes J.D. J. Clin. Investig. PubMed Scopus Google Scholar), indicating a mechanism dependent on However, LDLR degradation in hepatocytes expressed in J.D. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar), that the LDLR also endocytic and from the pathway. we a pool of LDLR in the that with N. D.A. Tebon A. S. J. Attie A.D. A. 2007; PubMed Scopus Google Scholar), a in this pathway. from this and a in of apoB and of the nascent VLDL particle in the from the ER, the VLDL particle is to binding the LDLR via apoB apoE, the the This is by a of the particle to the endocytic pathway for degradation. LDLR in this as a mechanism that in the and endocytic to the secretion of VLDL We L. for the for the and Davis and for of the L. for and the mice used in this and for with
Blasiole et al. (Thu,) studied this question.
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