Apolipoprotein[a] secretion from hepatoma cells is regulated in a size-dependent manner by alterations in disulfide bond formation

Apolipoprotein[a] (apo[a]) is a large disulfide linked glycoprotein synthesized by hepatocytes. We have examined the role of disulfide bond formation in the processing of apo[a] using human and rat hepatoma cells expressing apo[a] isoforms containing varying numbers of kringle 4 (K4) domains, following treatment with DTT. Hepatoma cells expressing 6- or 9-K4 isoforms revealed ∼90% inhibition of apo[a] secretion following DTT treatment, although larger isoforms containing 13- or 17-K4 domains demonstrated continued secretion (up to 30% of control values), suggesting that a fraction of the larger isoforms is at least partially DTT resistant. Wash-out experiments demonstrated that these effects were completely reversible for all isoforms studied, with no enhanced degradation associated with prolonged intracellular retention. DTT treatment was associated with enhanced binding of apo[a] with the endoplasmic reticulum-associated chaperone proteins calnexin, calreticulin, and BiP, which was reversible upon DTT removal. The chemical chaperone 6-aminohexanoic acid, previously demonstrated by others to rescue defective apo[a] secretion associated with alterations in glycosylation, failed to alter the secretion of apo[a] following DTT treatment.The demonstration that DTT modulates apo[a] secretion in a manner influenced by both the type and number of K4 repeats extends understanding of the mechanisms that regulate its exit from the endoplasmic reticulum. Apolipoprotein[a] (apo[a]) is a large disulfide linked glycoprotein synthesized by hepatocytes. We have examined the role of disulfide bond formation in the processing of apo[a] using human and rat hepatoma cells expressing apo[a] isoforms containing varying numbers of kringle 4 (K4) domains, following treatment with DTT. Hepatoma cells expressing 6- or 9-K4 isoforms revealed ∼90% inhibition of apo[a] secretion following DTT treatment, although larger isoforms containing 13- or 17-K4 domains demonstrated continued secretion (up to 30% of control values), suggesting that a fraction of the larger isoforms is at least partially DTT resistant. Wash-out experiments demonstrated that these effects were completely reversible for all isoforms studied, with no enhanced degradation associated with prolonged intracellular retention. DTT treatment was associated with enhanced binding of apo[a] with the endoplasmic reticulum-associated chaperone proteins calnexin, calreticulin, and BiP, which was reversible upon DTT removal. The chemical chaperone 6-aminohexanoic acid, previously demonstrated by others to rescue defective apo[a] secretion associated with alterations in glycosylation, failed to alter the secretion of apo[a] following DTT treatment. The demonstration that DTT modulates apo[a] secretion in a manner influenced by both the type and number of K4 repeats extends understanding of the mechanisms that regulate its exit from the endoplasmic reticulum. Apolipoprotein[a] (apo[a]) is a large and highly polymorphic glycoprotein whose interaction with apoB-100 results in the formation of an atherogenic lipoprotein particle referred to as lipoprotein[a] (Lp[a]) (1Berg K. A new serum type system in man-the Lp system.Acta Pathol. Microbiol. Scand. 1963; 59: 369-382Google Scholar, 2Hobbs H.H. White A.L. Lipoprotein(a): intrigues and insights.Curr. Opin. Lipidol. 1999; 10: 225-236Google Scholar, 3McCormick S.P. Ng J.K. Taylor S. Flynn L.M. Hammer R.E. Young S.G. Mutagenesis of the human apolipoprotein B gene in a yeast artificial chromosome reveals the site of attachment for apolipoprotein(a).Proc. Natl. Acad. Sci. USA. 1995; 92: 10147-10151Google Scholar, 4Utermann G. The mysteries of lipoprotein(a).Science. 1989; 246: 904-910Google Scholar). Both protein components of Lp[a] are synthesized by hepatocytes, although the production of apo[a] is confined to the liver of humans and certain primates while production of apoB-100 is universally observed in mammalian hepatocytes (5Kraft H.G. Menzel H.J. Hoppichler F. Vogel W. Utermann G. Changes of genetic apolipoprotein phenotypes caused by liver transplantation. Implications for apolipoprotein synthesis.J. Clin. Invest. 1989; 83: 137-142Google Scholar, 6Young S. Recent progress in understanding apolipoprotein B.Circulation. 1990; 82: 1574-1594Google Scholar). Elevated circulating levels of Lp[a] in humans is associated with increased risk for a number of atherosclerotic diseases, including coronary artery disease and stroke, and this association has driven continued interest in the mechanisms that regulate plasma levels of this enigmatic lipoprotein species (4Utermann G. The mysteries of lipoprotein(a).Science. 1989; 246: 904-910Google Scholar, 5Kraft H.G. Menzel H.J. Hoppichler F. Vogel W. Utermann G. Changes of genetic apolipoprotein phenotypes caused by liver transplantation. Implications for apolipoprotein synthesis.J. Clin. Invest. 1989; 83: 137-142Google Scholar, 7Kostner K.M. Kostner G.M. Lipoprotein(a): still an enigma?.Curr Opin Lipidol. 2002; 13: 391-396Google Scholar). Studies of the mechanisms underlying the remarkable genetic variability in Lp[a] levels in humans have demonstrated that differences largely reside in the production rate of this lipoprotein rather than changes in its catabolism (8Krempler F. Kostner G.M. Bolzano K. Sandhofer F. Turnover of lipoprotein (a) in man.J. Clin. Invest. 1980; 65: 1483-1490Google Scholar, 9Rader D.J. Cain W. Ikewaki K. Talley G. Zech L.A. Usher D. Brewer Jr., H.B. The inverse association of plasma lipoprotein(a) concentrations with apolipoprotein(a) isoform size is not due to differences in Lp(a) catabolism but to differences in production rate.J. Clin. Invest. 1994; 93: 2758-2763Google Scholar, 10Rader D.J. Cain W. Zech L.A. Usher D. Brewer Jr., H.B. Variation in lipoprotein(a) concentrations among individuals with the same apolipoprotein (a) isoform is determined by the rate of lipoprotein(a) production.J. Clin. Invest. 1993; 91: 443-447Google Scholar, 11White A.L. Hixson J.E. Rainwater D.L. Lanford R.E. Molecular basis for “null” lipoprotein(a) phenotypes and the influence of apolipoprotein(a) size on plasma lipoprotein(a) level in the baboon.J. Biol. Chem. 1994; 269: 9060-9066Google Scholar). These differences in production rate appear to be reproducible within individuals and are not subject to significant modulation by diet or pharmacologic manipulations directed at lowering plasma cholesterol levels (12Nawrocki J.W. Weiss S.R. Davidson M.H. Sprecher D.L. Schwartz S.L. Lupien P.J. Jones P.H. Haber H.E. Black D.M. Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor.Arterioscler. Thromb. Vasc. Biol. 1995; 15: 678-682Google Scholar, 13Bakker-Arkema R.G. Davidson M.H. Goldstein R.J. Davignon J. Isaacsohn J.L. Weiss S.R. Keilson L.M. Brown W.V. Miller V.T. Shurzinske L.J. Black D.M. Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia.JAMA. 1996; 275: 128-133Google Scholar). The most informative insight into the potential mechanisms regulating hepatic production of apo[a] derives from a series of studies demonstrating that variations at the APOA gene locus result in transcription of a variable number of copies of a repeating domain that resembles that of the kringle 4 (K4) found in plasminogen (14Boerwinkle E. Leffert C.C. Lin J. Lackner C. Chiesa G. Hobbs H.H. Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations.J. Clin. Invest. 1992; 90: 52-60Google Scholar, 15Brunner C. Lobentanz E. Petho-Schramm A. Ernst A. Kang C. Dieplinger H. Muller H. Utermann G. The number of identical kringle IV repeats in apolipoprotein(a) affects its processing and secretion by HepG2 Biol. Chem. 1996; Scholar, S. Kostner G.M. The role of in the of 10: Scholar, J.E. Rainwater D.L. Apolipoprotein(a) glycoprotein isoforms result from size differences in in Biol. Chem. 1989; Scholar, D. D.L. Apolipoprotein(a) size is to variable number of in its 1990; Scholar, C. Hobbs H.H. Molecular of the size in 1993; Scholar, K. A. C. Muller H.J. J. H.G. Utermann G. Dieplinger H. of human apolipoprotein(a) in Scholar). varying numbers of these repeats in plasma levels of Lp[a] are to the number of these domains K. A. C. Muller H.J. J. H.G. Utermann G. Dieplinger H. of human apolipoprotein(a) in Scholar, C. E. Leffert C.C. Hobbs H.H. Molecular basis of apolipoprotein (a) isoform size as revealed by Clin. Invest. Scholar). Studies by White and have demonstrated that the most for this is that apo[a] isoforms with larger numbers of K4 repeats a with and in the endoplasmic an and in the and secretion A.L. Hixson J.E. Rainwater D.L. Lanford R.E. Molecular basis for “null” lipoprotein(a) phenotypes and the influence of apolipoprotein(a) size on plasma lipoprotein(a) level in the baboon.J. Biol. Chem. 1994; 269: 9060-9066Google Scholar, J. J. Hobbs H.H. White A.L. of human apolipoprotein secretion from Scholar). has on understanding the control of apo[a] secretion from hepatocytes, and a of studies that the of apo[a] secretion is linked to its processing and exit rate from the endoplasmic with endoplasmic reticulum-associated degradation a role J. White A.L. of calnexin, calreticulin, and endoplasmic in apolipoprotein(a) intracellular Scholar). These are with studies demonstrating that alterations in the of apo[a] a role in its secretion and its interaction with chaperone proteins J. White A.L. of calnexin, calreticulin, and endoplasmic in apolipoprotein(a) intracellular Scholar, F. Davidson of results in of intracellular apo[a] in hepatoma although and of are to with apolipoprotein in Scholar). of J. White A.L. of calnexin, calreticulin, and endoplasmic in apolipoprotein(a) intracellular or apo[a] secretion F. Davidson of results in of intracellular apo[a] in hepatoma although and of are to with apolipoprotein in suggesting that alterations in or processing a role in the of apo[a] is with the that apo[a] is of the of the protein is G.M. of apolipoprotein(a) and from the of human plasma lipoprotein Biol. Chem. Scholar, J.E. Schwartz K. D.L. and of a of the protein in mammalian Scholar). to the of mechanisms to the and processing of the role of disulfide bond formation in regulating the secretion of apo[a] isoforms of The was on the that apo[a] disulfide in kringle J.W. J. D.L. G.M. of human apolipoprotein(a) is to and an to that in the of disulfide bond formation in the of secretion from hepatocytes H. are for and secretion of apolipoprotein B of its Biol. Chem. 275: Scholar, of disulfide bond formation in the and secretion of apolipoprotein 1996; Scholar). The that DTT treatment and modulates apo[a] secretion in a manner that is reversible and not by alterations in intracellular The results that DTT treatment apo[a] processing in a manner that both the number and type of K4 and and DTT were all from was from was from was from was from and were from was from for were from were from and were of the and from of HepG2 and cells expressing a apo[a] containing domains were as previously F. Davidson of results in of intracellular apo[a] in hepatoma although and of are to with apolipoprotein in Scholar, F. Davidson Apolipoprotein(a) and secretion from hepatoma cells is to and Biol. Chem. Scholar). cells were with apo[a] or 17-K4 repeats F. Davidson of results in of intracellular apo[a] in hepatoma although and of are to with apolipoprotein in Scholar, F. Davidson Apolipoprotein(a) and secretion from hepatoma cells is to and Biol. Chem. Scholar). The apo[a] was by K. A. C. Muller H.J. J. H.G. Utermann G. Dieplinger H. of human apolipoprotein(a) in Scholar). These are to the by and for K4 repeats A. of of apo[a] in human Thromb. 1993; Scholar). HepG2 cells were in with and cells were in containing 4 and HepG2 and cells were to 90% in to the cells were with for in and in the same containing and in containing and for the in the was no with DTT. and were with which was to experiments were using in the following the cells were to and with in for to intracellular of disulfide bond formation in the and secretion of apolipoprotein 1996; Scholar). were and a of was The cells were with and in containing with and were by at at for to and were as were as F. Davidson of results in of intracellular apo[a] in hepatoma although and of are to with apolipoprotein in Scholar, F. Davidson Apolipoprotein(a) and secretion from hepatoma cells is to and Biol. Chem. Scholar). were with of or of was to a of and was to and and at at protein were and the continued for at The was in in The were for in and the was by and was using a Molecular and the The binding of calnexin, calreticulin, and to the of apo[a] was determined as by F. Davidson of results in of intracellular apo[a] in hepatoma although and of are to with apolipoprotein in Scholar). cells expressing the apo[a] isoform were to 90% in The cells were for in and and in the same containing of cells was in containing and DTT for to of cells was in the of DTT for which DTT was by in and the cells were in DTT for the in the the of cells were to and with in for of disulfide bond formation in the and secretion of apolipoprotein 1996; Scholar). The cells were with and in and as cells were in by the of and for at were in with a to calnexin, calreticulin, or The from the was using protein A and in The protein A was for in containing the was with of and for with apo[a] were by and studies have demonstrated that alterations in result in of apo[a] within the endoplasmic and or secretion of isoforms J. White A.L. of calnexin, calreticulin, and endoplasmic in apolipoprotein(a) intracellular Scholar, F. Davidson of results in of intracellular apo[a] in hepatoma although and of are to with apolipoprotein in Scholar). to the role of disulfide bond formation as a to regulate and processing of HepG2 cells expressing a isoform were to in the of using the by and and and of disulfide bond formation in the and secretion of apolipoprotein 1996; Scholar, The is in but proteins are and in the endoplasmic Biol. Chem. 1993; Scholar). The isoform has previously demonstrated to processing and secretion by hepatoma cells and was for F. Davidson of results in of intracellular apo[a] in hepatoma although and of are to with apolipoprotein in Scholar, F. Davidson Apolipoprotein(a) and secretion from hepatoma cells is to and Biol. Chem. Scholar). in DTT treatment secretion of apo[a] into the and to of the within of apo[a] 90% in control cells and in DTT cells of suggesting that the intracellular of apo[a] following DTT treatment was not by increased of was in with intracellular as previously H. are for and secretion of apolipoprotein B of its Biol. Chem. 275: Scholar, of disulfide bond formation in the and secretion of apolipoprotein 1996; Scholar). A series of experiments were to the effects of DTT treatment on the of and secretion of apo[a] were HepG2 cells expressing the isoform were using a in in the to a and in the of cells were and for a in the of DTT. The results following of apo[a] and is in a manner to that demonstrated in to the effects of DTT on the processing and secretion of apo[a] to rat hepatoma cells as a of these cells with larger isoforms of apo[a] to that the protein at levels that studies F. Davidson of results in of intracellular apo[a] in hepatoma although and of are to with apolipoprotein in Scholar, F. Davidson Apolipoprotein(a) and secretion from hepatoma cells is to and Biol. Chem. as as in studies by others K. A. C. Muller H.J. J. H.G. Utermann G. Dieplinger H. of human apolipoprotein(a) in HepG2 cells for the larger apo[a] as by the for apo[a] in studies K. A. C. Muller H.J. J. H.G. Utermann G. Dieplinger H. of human apolipoprotein(a) in Scholar). have on the of of human expressing apo[a] J. J. Hobbs H.H. White A.L. of human apolipoprotein secretion from Scholar). to cells expressing apo[a] isoforms with or 17-K4 repeats which were subject to in the or of DTT. The results that DTT secretion of all isoforms of although a greater of the larger isoforms and was in to the 6- and 9-K4 isoforms of the effects of DTT treatment appear confined to proteins that disulfide the secretion of a protein with a and no disulfide was by of DTT The results of experiments in which was in the or of DTT in the that of DTT in both the and secretion of the isoform by with the from HepG2 cells secretion of apo[a] isoforms containing 13- or 17-K4 repeats was to of control the experiments demonstrated in that the effects of DTT are reversible for all apo[a] and secretion cells were in the of DTT and in the of DTT and both DTT to the DTT but the no A series of experiments was to the effects of concentrations of DTT on the secretion of the isoform from These studies revealed that of concentrations of DTT secretion of the apo[a] isoform These that the of apo[a] isoforms containing the K4 type domain and concentrations of DTT to disulfide bond formation and secretion than the isoforms and Studies that the effects of DTT are to the of studies were in cells expressing apo[a] isoforms in which and studies were in the of by a and a in the of DTT. The results as in HepG2 apo[a] isoforms containing or 17-K4 repeats with of secretion following the of DTT these studies that the to secretion of the larger isoforms is than that observed for the isoforms for the for the for the 4 The for apo[a] secretion following DTT is to that observed in cells to DTT F. Davidson of results in of intracellular apo[a] in hepatoma although and of are to with apolipoprotein in Scholar, F. Davidson Apolipoprotein(a) and secretion from hepatoma cells is to and Biol. Chem. the that the effects of DTT on apo[a] secretion are completely reversible for all a of the size of apo[a] from cells expressing a or isoform were examined in the of DTT. apo[a] was by with or in to the of the with to of in apo[a] from the isoform its of apo[a] from the isoform revealed but reproducible changes in of These with the in that the and of apo[a] size that in the number of K4 cells expressing a or isoform of apo[a] were for or and for 4 with DTT at the of The results of this that secretion of apo[a] is following DTT at to for the isoform control to secretion of the isoform to DTT treatment to into the control to of DTT to the in inhibition the effects at to for the and to for the These with the in the differences in of the and apo[a] isoforms that is a for which disulfide bond formation be by the of DTT. this the effects of DTT suggesting that disulfide bond formation is and for these to the secretion of apo[a] in and C. of of the isoform for secretion has in the with for the in the of the DTT to cells at of reveals effects on apo[a] secretion suggesting that of this isoform is largely the DTT to cells expressing the isoform at of apo[a] secretion to of control levels the in that of the for secretion in the at this in These to differences in processing and as the for DTT inhibition of secretion rather than the of of apo[a] with secretion studies have demonstrated that alterations in apo[a] processing as a result of in are associated with changes in the of association of the with chaperone including calnexin, calreticulin, and J. White A.L. of calnexin, calreticulin, and endoplasmic in apolipoprotein(a) intracellular Scholar, F. Davidson of results in of intracellular apo[a] in hepatoma although and of are to with apolipoprotein in Scholar). to the mechanisms underlying the alterations in secretion of apo[a] in the of studies were using cells expressing a isoform in which the association of synthesized apo[a] with these chaperone proteins was examined by were for and for to in the of following which a was for in the of DTT The results of these studies that apo[a] with calnexin, calreticulin, and the in the of DTT the of apo[a] was demonstrated in these with previously J. White A.L. of calnexin, calreticulin, and endoplasmic in apolipoprotein(a) intracellular Scholar, F. Davidson of results in of intracellular apo[a] in hepatoma although and of are to with apolipoprotein in Scholar). of the association of apo[a] with all chaperone proteins examined was found to in with the as as of the of apo[a] in the studies from White and have demonstrated that the 6-aminohexanoic the secretion of apo[a] from hepatocytes and the inhibition of apo[a] secretion by inhibition of by J. White A.L. as a chemical chaperone for Biol. Chem. 1999; Scholar). The effects of this chemical chaperone were by these to enhanced of exit of the glycoprotein from the endoplasmic J. White A.L. of calnexin, calreticulin, and endoplasmic in apolipoprotein(a) intracellular Scholar, J. White A.L. as a chemical chaperone for Biol. Chem. 1999; Scholar). to this chemical chaperone a on the secretion of an or apo[a] following alterations in disulfide bond cells expressing a isoform were by as in the of were for in the of the and for or 4 an of both intracellular apo[a] processing and its secretion and were the results demonstrating the following as previously demonstrated in hepatocytes expressing a human 17-K4 apo[a] J. White A.L. as a chemical chaperone for Biol. Chem. 1999; apo[a] secretion into the from cells expressing a apo[a] isoform and treatment with results in a in apo[a] secretion and and this was by the of and These are in with the from White and hepatocytes from to apo[a] secretion in to alterations in J. White A.L. as a chemical chaperone for Biol. Chem. 1999; Scholar). and in to these the inhibition of apo[a] secretion following DTT treatment was not by treatment and the that treatment apo[a] secretion in the of but that the same rescue to be to exit from the endoplasmic not apo[a] of disulfide to be in the same The results of these studies that isoforms of apo[a] informative to treatment with that for of the protein in and its The experiments were using an isoform of apo[a] that of the K4 domains found in but of the repeating type domains that are the of apo[a] size C. E. Leffert C.C. Hobbs H.H. Molecular basis of apolipoprotein (a) isoform size as revealed by Clin. Invest. Scholar, C. Davidson of a apolipoprotein(a) in HepG2 for intracellular of Biol. Chem. Scholar). The apo[a] isoform has previously in HepG2 cells and certain of the including its to with its for and processing and its intracellular degradation within the endoplasmic F. Davidson of results in of intracellular apo[a] in hepatoma although and of are to with apolipoprotein in Scholar, F. Davidson Apolipoprotein(a) and secretion from hepatoma cells is to and Biol. Chem. Scholar, C. Davidson of a apolipoprotein(a) in HepG2 for intracellular of Biol. Chem. Scholar). of the isoform be as of the isoforms of in of the of the repeating domains that these of the of this was to of the inverse apo[a] size and its secretion in of the that kringle domain disulfide that of with DTT be informative with to the of apo[a] by the apo[a] isoform and the The results that secretion of the isoforms containing 6- or 9-K4 repeats is following DTT treatment, while is of secretion of the larger isoforms containing and 17-K4 species of the to DTT appear to be the and larger both and larger isoforms of the effects of the and in DTT These the greater of for the larger isoforms to DTT are with the a that apo[a] isoforms containing larger numbers of K4 domains to the effects of DTT than isoforms with K4 The that DTT is for at least or the of with the and the that disulfide bond formation in in a rather than is with the that the for of the larger isoforms in of the the type into a the results of these experiments not that disulfide bond formation in the larger isoforms to is this or in within or kringle studies from White and using hepatocytes demonstrated that the of disulfide bond with with a of that A.L. Lanford R.E. of variation on apolipoprotein(a) in the endoplasmic Biol. Chem. Scholar). These found no differences in the or of with isoforms of results using size of apo[a] no apo[a] was in in to the of White and A.L. Lanford R.E. of variation on apolipoprotein(a) in the endoplasmic Biol. Chem. Scholar). We that the differences these be by differences in the rat hepatoma cells in these to from these studies is that the of DTT to a in apo[a] secretion that greater in the isoforms the at least were in this that the larger by of the greater numbers of disulfide greater to the of by a inhibition of be to the effects with which to a secretion of the isoform from cells but completely secretion of larger isoforms containing 9-K4 and 17-K4 repeats F. Davidson of results in of intracellular apo[a] in hepatoma although and of are to with apolipoprotein in Scholar). The was that of the larger isoforms in a manner that certain to is with the that the of a of intracellular apo[a] to the effects of DTT and the continued at control of the in with the larger isoform for the the basis for differences to be be that while all the isoforms K4 the larger isoforms of the repeating domain in the of the the that this domain is to in disulfide bond is as to that of the larger isoforms than the which in domains in the the to into a These are in the in be the effects of DTT on apo[a] secretion and the effects of this on the secretion of A series of studies by the of and and by and has the of species to in to secretion and to and degradation H. are for and secretion of apolipoprotein B of its Biol. Chem. 275: Scholar, of disulfide bond formation in the and secretion of apolipoprotein 1996; Scholar, of the domain of apolipoprotein B to Biol. Chem. Scholar). the of apoB-100 of the disulfide and studies using species or have demonstrated that DTT is within H. are for and secretion of apolipoprotein B of its Biol. Chem. 275: Scholar, of the domain of apolipoprotein B to Biol. Chem. Scholar). and demonstrated continued secretion of apoB-100 from HepG2 cells to DTT in both the and at levels of disulfide bond formation in the and secretion of apolipoprotein 1996; Scholar). The results an role for the of apoB-100 in a and that in a fraction of the protein to DTT resistant. The of the to that domains in the larger isoforms the of a DTT is with that concentrations of DTT the inhibition of apo[a] secretion with with the studies in the results no for a of the to reversible with changes in apoB-100 following DTT treatment and is of disulfide bond formation in the and secretion of apolipoprotein 1996; Scholar). The results that all the isoforms studied, including the 17-K4 isoform that is larger than completely reversible inhibition of and of secretion to levels observed with in this is the that was no in intracellular degradation associated with prolonged retention. the for the of degradation is the prolonged and enhanced binding by the chaperone proteins in DTT These are in with the results of studies from White and demonstrated that degradation of apo[a] in hepatocytes be that its interaction with J. White A.L. of calnexin, calreticulin, and endoplasmic in apolipoprotein(a) intracellular Scholar, A.L. Lanford R.E. of variation on apolipoprotein(a) in the endoplasmic Biol. Chem. Scholar). this the studies of White and demonstrated that the chemical chaperone the in apo[a] secretion associated with treatment of hepatocytes J. White A.L. as a chemical chaperone for Biol. Chem. 1999; Scholar). The that this exit from the endoplasmic of apo[a] following DTT treatment, suggesting that informative proteins following that be to the of the reversible of apo[a] species in liver cells of its the These and be the of These studies were by from the of and the of