help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nguyen, T. T.
Right arrow Articles by O’Brien, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nguyen, T. T.
Right arrow Articles by O’Brien, T.
The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 11 4354-4358
Copyright © 2000 by The Endocrine Society

Original Studies

Familial Splenomegaly: Macrophage Hypercatabolism of Lipoproteins Associated with Apolipoprotein E Mutation [Apolipoprotein E ({Delta}149 Leu)]

Tu T. Nguyen, Kent E. Kruckeberg, John F. O’Brien, Zhong-Sheng Ji, Pamela S. Karnes, Thomas B. Crotty, Ian D. Hay, Robert W. Mahley and Timothy O’Brien

Divisions of Endocrinology (T.T.N., T.O., I.D.H.), Molecular Genetics (K.E.K., J.F.O.), Medical Genetics (P.S.K.), and Laboratory Medicine and Pathology (T.B.C.), Mayo Clinic and Foundation, Rochester, Minnesota 55905; and Gladstone Institute of Cardiovascular Disease (Z.-S.J., R.W.M.), Cardiovascular Research Institute, and Departments of Pathology and Medicine (R.W.M.), University of California, San Francisco, California 94141

Address all correspondence and requests for reprints to: Tu T. Nguyen, M.D., Division of Endocrinology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. E-mail: nguyen.tu{at}mayo.edu


   Abstract
Top
 Abstract
Introduction
 Case Reports
 Discussion
 References
 
Splenomegaly with sea-blue histiocytes is not associated with dyslipidemia, except in severe cases of hypertriglyceridemia, Tangier disease, or lecithin cholesterol acyltransferase deficiency. We describe two kindreds in which the sea-blue histiocyte syndrome was associated with an apoE variant in the absence of severe dyslipidemia. Both patients presented with mild hypertriglyceridemia and splenomegaly. After splenectomy both patients developed severe hypertriglyceridemia. Pathological evaluation of the spleen revealed the presence of sea-blue histiocytes. A mutation of apoE was demonstrated, with a 3-bp deletion resulting in the loss of a leucine at position 149 in the receptor-binding region of the apoE molecule [apoE ({Delta}149 Leu)]. Although both probands were unrelated, they were of French Canadian ancestry, suggesting the possibility of a founder effect. In summary, we describe two unrelated probands with primary sea-blue histiocytosis who had normal or mildly elevated serum triglyceride concentrations that markedly increased after splenectomy. In addition, we provide evidence linking the syndrome to an inherited dominant mutation in the apoE gene, a 3-bp deletion on the background of an apoE 3 allele that causes a derangement in lipid metabolism and leads to splenomegaly in the absence of severe hypertriglyceridemia.


   Introduction
Top
 Abstract
 Introduction
Case Reports
 Discussion
 References
 
SEA-BLUE HISTIOCYTOSIS (1) describes splenomegaly in the presence of numerous histiocytes stained a sea-blue color. This finding occurs in several conditions, including cholesterol ester storage disease and other lysosomal disorders, Niemann-Pick variant, Gaucher disease, severe hypertriglyceridemia (>11.36 mmol/L), lecithin-cholesterol acyltransferase deficiency, and Tangier disease (2). The primary syndrome of sea-blue histiocytosis has no known etiology, although a biochemical derangement in lipid metabolism has been hypothesized (2). One of the major apolipoproteins controlling lipoprotein metabolism is apolipoprotein E (apoE) (3), a 34,000 molecular mass protein that is associated with various lipoproteins and serves as a ligand for the low density lipoprotein (LDL) receptor. There are three common isoforms, apoE2, apoE3, and apoE4. Whereas apoE3 is considered to be the normal form, apoE2 and other apoE variants are defective in receptor binding, which leads to type III hyperlipoproteinemia and accumulation of remnant lipoproteins, ß-migrating very low density lipoproteins (ß-VLDL) (3, 4). Splenomegaly has not been associated with this lipid disorder, except in cases of severe hypertriglyceridemia (5).

We describe two unrelated probands with primary sea-blue histiocytosis who had normal or mildly elevated serum triglyceride (TG) concentrations that increased markedly after splenectomy. We provide evidence linking the syndrome to an inherited dominant mutation in the apoE gene, a 3-bp deletion on the background of an apoE3 allele that causes a derangement in lipid metabolism and leads to splenomegaly in the absence of severe hypertriglyceridemia.


   Case Reports
Top
 Abstract
 Introduction
 Case Reports
Discussion
 References
 
Proband 1

Proband 1, a 29-yr-old healthy white man, was found to have splenomegaly on routine examination. His total cholesterol (TC) was 2.32 mmol/L with TG of 2.09 and high density lipoprotein cholesterol (HDL-C) of 0.54 mmol/L (Table 1Go). His aspartate aminotransferase level was 40 U/L (normal, 12–31), and platelet count was 140,000/L (normal, 184,000–370,000). The work-up for infection and malignancy was negative. Computed tomography (CT) of the abdomen showed splenomegaly and fatty infiltration of the liver. Splenectomy was performed. The spleen measured 24 x 22 x 10 cm and weighed 1200 g (normal, 70–250). The red pulp was markedly expanded by foamy histiocytes (Fig. 1Go); the white pulp was normal. Transmission electron microscopy of the spleen showed curvilinear lamellae (fingerprint bodies; Fig. 2Go). Liver biopsy showed severe macrovesicular steatosis without fibrosis. Enzyme analyses for acid cholesteryl ester hydrolase, {alpha}-mannosidase, arylsulfatase, ß-galactosidase, ß-glucocerebrosidase, cerebroside ß-galactosidase, sphingomyelinase, and hexosaminidase were within normal limits, as were urinary acid mucopolysaccharides.


View this table:
[in this window]
[in a new window]
  		Table 1. Postsplenectomy hyperlipidemia associated with ApoE variant

 


View larger version (155K):
[in this window]
[in a new window]
  		Figure 1. Photomicrograph of the spleen showing expansion of the red pulp by foamy histiocytes (hematoxylin and eosin staining; magnification, x85).

 


View larger version (170K):
[in this window]
[in a new window]
  		Figure 2. Transmission electron micrographs of the spleen showing fingerprint inclusion within a foamy histiocyte. Bar = 0.25 µm.

 
Three months after splenectomy, TC was 4.75, TG was 2.48, and HDL-C was 0.59 mmol/L. Ultracentrifugation and electrophoretic analysis of fasting lipoproteins showed no chylomicrons, increased ß-VLDL, and a VLDL-C/plasma TG ratio of 0.21. One year after the surgery, TC was 5.17, TG was 7.27, and HDL-C was 0.49 mmol/L (Table 1Go).

The patient was referred to our lipid clinic. There was no evidence of alcohol abuse, weight increase, or dietary change. His height was 176 cm, and he weighed 84.4 kg. There was no xanthoma or hepatomegaly, and ophthalmological examination was normal. Plasma glucose, kidney, and thyroid function tests were normal. A low fat diet and gemfibrozil (1200 mg daily) were prescribed. After 3 months, TG had decreased to 2.31 mmol/L. TC and HDL-C were 6.56 and 0.85 mmol/L, respectively. Over the next 2 yr, while taking gemfibrozil, TG fluctuated, rising to a maximum of 5.68 mmol/L with dietary noncompliance.

Because of the presence of ß-VLDL on lipoprotein analysis, apoE genotyping was performed. A portion of exon 4 of the apoE gene was amplified with primers that flank the apoE2, apoE3, and apoE4 polymorphisms. The sequences were: apoE-A, CGG-GCA-CGG-CTG-TCC-AAG-GAG; and apoE-C, CAC-GCG-GCC-CTG-TTC-CAC-CAG. Nondenaturing 8% PAGE of the HhaI digest revealed a triplet in the region of the 48-bp fragment normally found in the apoE3 and apoE4 alleles. Sequencing (fmol DNA cycle sequencing system kit, Promega Corp., Madison, WI) this area from each direction with the same primers showed a 3-bp deletion corresponding to the codon for leucine at position 149 of the E3 allele [apoE3({Delta}149 Leu); Fig. 3Go]. The other allele was apoE3. ApoE isoelectric focusing showed an apoE3/E3 pattern. Pre- and postheparin lipoprotein lipase (LPL) activities (6) (courtesy of R. Eckel, University of Colorado Health Sciences Center, Denver, CO) were 4.3 (95% confidence interval, 0.6–29.8) and 1366.9 nEq free fatty acid/mL·h (95% confidence interval, 1569–10176), respectively, whereas hepatic lipase activity was normal. An Asn291->Ser mutation in the LPL gene (heterozygous) was identified in this patient using a previously described method (7). Three other common LPL mutations (Asp250->Asn, Gly188->Glu, and Pro207->Leu) were not detected. Review of the pedigree showed maternal French-Canadian ancestry. There was a strong family history of cardiovascular disease. The mother of proband 1 had the same apoE defect (the other allele was E2) and the same heterozygous LPL gene mutation. She had type 2 diabetes and documented ischemic heart disease. TC was 4.55, TG was 1.67, and HDL-C was 1.21 mmol/L. CT showed a spleen of generous size with an estimated volume of 523 cc (normal range, 78–198 cc).



View larger version (81K):
[in this window]
[in a new window]
  		Figure 3. DNA sequencing of exon 4. Lane A, Proband 1; lane B, apoE2 homozygous; lane C, apoE3 homozygous; lane D, apoE4 homozygous. The nucleotide sequence of the normal alleles is displayed on the left. The sequence resulting from the 3-bp deletion is indicated on the right.

 
Although the proband had no cardiac symptoms, an Electron Beam CT scan of the heart showed one dominant focus of calcification in the left anterior descending coronary artery. This amount of calcification placed him in the top 10% of his age and gender for the quantity of calcification.

Proband 2

Proband 2, a 49-yr-old healthy white man, was found on routine examination to have elevated serum alanine amino- transferase (121 U/L; normal, 58–116). Alcohol intake was minimal, and hepatitis serology was negative. Splenomegaly was noted and confirmed by CT. Bone marrow biopsy revealed normocellular marrow. Splenectomy was performed for thrombocytopenia (platelet count, 112,000/L) at another institution. Four years before splenectomy, his TC ranged from 3.72–3.80 and TG from 2.53–4.31 mmol/L (Table 1Go). The spleen measured 21 x 17 x 7 cm and weighed 1024 g. There was expansion of the red pulp with marked splenic cord infiltration by numerous foamy cells, consistent with sea-blue histiocytosis. Postoperatively, TC and TG were 5.68 and 12.90 mmol/L, respectively.

The patient was referred to our lipid clinic. He was asymptomatic and had no recent weight change. His height was 179 cm, and he weighed 84.7 kg. The remainder of the examination was unremarkable. Aminotransferase was 36 mg/dL (normal, 12–31). TC was 6.54, TG was 15.59, and HDL-C was 0.67 mmol/L (Table 1Go). The plasma apoE concentration (8) was 11.5 mg/dL (normal mean, 5.1 ± 1.6), with a normal apoCII concentration. The work-up for known causes of splenomegaly and sea-blue histiocytosis was negative. A low fat diet and gemfibrozil (1200 mg daily) were prescribed. After 3 months of this treatment, TG decreased to 6.52 mmol/L, TC was 6.62, and HDL-C was 0.64 mmol/L.

Lipoprotein analysis showed the presence of ß-VLDL and a VLDL-C/plasma TG ratio of 0.33. Plasma apoE decreased to 7.7 mg/dL. ApoE genotyping and sequencing showed the same 3-bp deletion as that identified in proband 1. The other allele was apoE3. None of the four common LPL mutations described above was detected.

Review of the pedigree showed both maternal and paternal French-Canadian ancestry. The parents were not consanguineous. The proband had two brothers with splenomegaly and TG levels of 2.34–2.86 and 3.01–11.53 mmol/L, respectively. There was a strong family history of cardiovascular disease. Five years after the initial evaluation, the proband developed symptoms of angina and underwent cardiac catheterization elsewhere that demonstrated a moderate 50–70% lesion of the left anterior descending coronary artery.

Functional assays of the apoE3 leucine deletion

ApoE was prepared from proband 1’s less than 1.02 g/mL density lipoproteins (9). However, the normal apoE3 and the deletion mutant could not be separated from one another. The mixture was subjected to a competitive receptor binding assay using dimyristoylphosphatidylcholine complexes (10) and [125I]LDL as competitor (11). The 100% competition point was 8.2 ng [125I]LDL bound. The binding assay demonstrated that the subject’s apoE bound to LDL receptors with the same affinity as normal apoE3 (ED50 = 0.062 µg/mL). Even though the subject’s apoE was a mixture of normal and mutant apoE, any significant binding defect would have been detected by this method.

The less than 1.006 density lipoproteins from proband 1 [apoE ({Delta}149 Leu)] were incubated with mouse macrophages to determine their ability to induce cholesterol esterification and were compared with less than 1.006 density lipoproteins from normolipidemic apoE3/3 and apoE2/2 subjects, a type III apoE2/2 subject, and a cholesterol-fed rabbit. The peritoneal macrophages of the mice (ICR strain) were harvested as previously described (12), plated, and maintained in DMEM containing 20% FBS for 24 h. The medium was changed to one supplemented with 10% lipoprotein-deficient plasma for 16 h. The macrophages were incubated with the lipoproteins (10 µg protein/mL) at 37 C for 5 h. Then, [14C]oleate/BSA complex was added, and the cells were incubated for an additional 3 h. After incubation, the esterified cholesterol in the macrophages was extracted, separated by thin layer chromatography, and quantitated (13). Significantly more [14C]oleate was incorporated after incubation with less than 1.006 density lipoproteins from the proband than from the apoE3/3 or apoE2/2 subjects (Fig. 4Go). The proband’s less than 1.006 density lipoproteins were as effective as the highly active rabbit ß-VLDL in inducing cholesterol esterification in mouse macrophages.



View larger version (28K):
[in this window]
[in a new window]
  		Figure 4. Cholesterol esterification in murine peritoneal macrophages. The macrophages were incubated with less than 1.006 density lipoproteins (10 mg lipoprotein protein/mL) obtained from the various subjects, and cholesterol ester formation in the cells was determined by measuring the amount of [14C]cholesteryl oleate formed (see text). The cholesterol to protein ratios of the less than 1.006 density lipoproteins were as follows: ß-VLDL with apoE({Delta}149 Leu), 8.2; ß-VLDL with apoE2/2, 8.4; VLDL from normolipidemic individuals with apoE3/3 or apoE2/2, 2.5 and 2.2, respectively; and rabbit ß-VLDL, 55. The data are the mean ± SD of values from one experiment performed in triplicate.

 

   Discussion
Top
 Abstract
 Introduction
 Case Reports
 Discussion
References
 
Splenomegaly with sea-blue histiocytes is not associated with dyslipidemia, except in severe hypertriglyceridemia (14), Tangier disease, or lecithin and cholesterol acyltransferase deficiency (15). We studied two kindreds in which the sea-blue histiocyte syndrome was associated with an apoE variant in the absence of severe dyslipidemia. Neither proband had biochemical or clinical features associated with LCAT deficiency or any known lipid storage disease. Although unrelated, both probands had French-Canadian ancestry, suggesting the possibility of a founder effect. The expression of the apoE mutation appears to be dominant. The 3-bp deletion results in the loss of a leucine at position 149 in the receptor-binding region (residues 130–150) (3, 4, 16) of the apoE molecule [apoE ({Delta}149 Leu)]. Unlike other previously described apoE variants associated with hyperlipoproteinemia, the apoE ({Delta}149 Leu) does not involve an arginine or lysine substitution. A similar mutation causing a deletion of leucine at position 149 has been described in another subject (TC, 4.06; TG, 0.94; HDL-C, 0.90 mmol/L), but no clinical findings were reported (17). Another apoE mutation, apoE1 (Gln156-Gly173->0) has recently been found to be related to lipoprotein glomerulopathy (18).

ApoE serves as a ligand for the clearance of VLDL and chylomicron remnants via lipoprotein receptors. The LDL receptor and the LDL receptor-related protein (LRP) interact with apoE-containing lipoproteins and are widely distributed, including in liver (19), spleen (20), and macrophages (21). Hussain et al. (22) have shown that macrophages in the bone marrow and spleen can play a role in the clearance of chylomicrons, and in some species, possibly including humans, the spleen and bone marrow combined are the second most common sites of clearance after the liver.

The less than 1.006 density lipoproteins possessing the apoE ({Delta}149 Leu) induced a marked accumulation of cholesteryl esters in mouse macrophages compared with VLDL from apoE3/3 and apoE2/2 normolipidemic individuals or with ß-VLDL from an apoE2/2 subject with type III hyperlipoproteinemia. The results obtained with the apoE ({Delta}149 Leu)-containing ß-VLDL were similar to those obtained with ß-VLDL from a cholesterol-fed rabbit. The lipoproteins were added to the cells on the basis of equal lipoprotein (10 µg protein/mL), although the less than 1.006 density lipoproteins differed in overall chemical composition and cholesterol to protein ratios. As indicated in the figure legend, the ß-VLDL with apoE ({Delta}149 Leu) and type III hyperlipoproteinemia apoE2/2 individuals had virtually identical cholesterol/protein ratios of 8.4 and 8.2, respectively, but these resulted in quite different cholesteryl ester formation. On the other hand, the rabbit ß-VLDL contained much more cholesterol than the ß-VLDL with apoE ({Delta}149 Leu), yet they were similar in the amount of intracellular cholesteryl esters that were induced. Although we could not evaluate directly LDL receptor binding of apoE ({Delta}149 Leu) because the patient was heterozygous for apoE3 and apoE ({Delta}149 Leu), the LDL receptor binding data are consistent with normal binding in the presence of the variant apoE. Nevertheless, the less than 1.006 density lipoproteins from the individual with the apoE ({Delta}149 Leu) caused a 3-fold enhancement in cholesteryl ester formation in the macrophages compared with VLDL from the apoE3/3 individual. Thus, it is demonstrated from these comparisons that the less than 1.006 density lipoprotein possessing apoE ({Delta}149 Leu) resulted in enhanced uptake by the peritoneal macrophages. Our study does not identify which specific receptor (LDL, LRP, lipolysis-stimulated receptor, or scavenger) is involved in the enhanced uptake. In addition, we cannot exclude the possibility that the mutant apoE renders the lipoproteins more susceptible to oxidation and subsequent uptake by scavenger receptors such as CD36, LOX-1, and CD68 receptor. Further studies will be needed to answer these questions.

The increased uptake of mutant apoE-containing lipoproteins by macrophages could be responsible for the splenomegaly in our two probands. Therefore, the enhanced macrophage uptake could have contributed to the relatively normal plasma lipid levels presplenectomy. This is especially striking in proband 1, whose TG was normal presplenectomy despite having low LPL activity due to a heterozygous LPL Asn291->Ser mutation. His mother also had normal TG in the presence of the same apoE variant and LPL mutation and an intact spleen that was generous in size. In proband 1, the development of splenomegaly may have been accelerated by the presence of partial LPL deficiency. Although splenomegaly was the initial clinical manifestation in both of our patients, the fact that both probands had evidence of premature coronary atherosclerosis suggest that the targeting is not specific to splenic macrophages. In addition, the observed hepatosteatosis could also be due to the hypercatabolism of mutant apoE-containing lipoproteins by hepatocytes.

The marked increase in plasma TG and TC and the presence of ß-VLDL postsplenectomy in our probands suggest that removal of the spleen allowed lipoproteins and their remnants to accumulate in the plasma. The presence of the LPL mutation in proband 1 may have accentuated the defect after the spleen was removed. However, partial LPL deficiency caused by the Asn291->Ser mutation is usually associated with only mild hypertriglyceridemia. The more severe hypertriglyceridemia that was unmasked postsplenectomy could be explained by either 1) a slight binding defect to the LDL receptor by the mutant apoE that could not be detected in our assay because a mixture of normal and mutant apoE was tested rather than the purified mutant, or 2) an abnormal interaction of the mutant apoE with heparan sulfate proteoglycan or with the LRP. This would cause defective sequestration of lipoprotein remnants in the space of Disse or defective internalization by LRP.

Our findings call attention to a new etiology for sea-blue histiocytosis and point out that the 149 variant of apoE appears to stimulate cholesterol ester accumulation in macrophages and could be associated with targeting of lipoproteins to macrophages. Splenectomy unmasked the lipoprotein defect and allowed expression of the hyperlipidemia and accumulation of remnant lipoproteins.


   Acknowledgments
 
We thank Ms. Patrice Abell-Aleff for her assistance with the electron microscopy, Dr. Gerry H. Tan for referring proband 1 to us, Sylvia Richmond for manuscript preparation, and Gary Howard and Stephen Ordway for editorial assistance.

Received March 10, 2000.

Revised July 27, 2000.

Accepted July 31, 2000.


   References
Top
 Abstract
 Introduction
 Case Reports
 Discussion
 References
 

  1. Silverstein MN, Ellefson RD, Ahern EJ. 1970 The syndrome of the sea-blue histiocyte. N Engl J Med. 282:1–4.
  2. Silverstein MN, Ellefson RD. 1972 The syndrome of the sea-blue histiocyte. Semin Hematol. 9:299–307.
  3. Mahley RW. 1988 Cholesterol transport protein with expanding role in cell biology. Science. 240:622–630.[Abstract/Free Full Text]
  4. Mahley RW, Rall Jr SC. 1995 Type III hyperlipoproteineimia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill; 1953–1980.
  5. Roberts WC, Levy RI, Fredrickson DS. 1970 Hyperlipoproteinemia. A review of the five types with first report of necropsy findings in type 3. Arch Pathol. 90:46–56.[Medline]
  6. Glaser DS, Yost TJ, Eckel RH. 1992 Preheparin lipoprotein lipolytic activities: relationship to plasma lipoproteins and postheparin lipolytic activities. J Lipid Res. 33:209–214.[Abstract]
  7. Minnich A, Kessling A, Roy M. 1995 Prevalence of alleles encoding defective lipoprotein lipase in hypertriglyceridemic patients of French Canadian descent. J Lipid Res. 36:117–124.[Abstract]
  8. Au YPT, Bren ND, Kottke BA. 1986 A rapid apolipoprotein E radioimmunoassay using solid-phase staphylococcus protein. Use of pooled plasma as a secondary standard. Biochem Biophys Res Commun. 138:455–462.[CrossRef][Medline]
  9. Rall Jr SC, Weisgraber KH, Mahley RW. 1986 Isolation and characterization of apolipoprotein E. Methods Enzymol. 128:273–287.[Medline]
  10. Innerarity TL, Pitas RE, Mahley RW. 1979 Binding of arginine-rich (E) apoprotein after recombination with phospholipid vesicles to the low density lipoprotein receptors of fibroblasts. J Biol Chem. 254:4186–4190.[Free Full Text]
  11. Innerarity TL, Mahley RW. 1978 Enhanced binding by cultured human fibroblasts of apo-E-containing lipoproteins as compared with low density lipoproteins. Biochemistry. 17:1440–1447.[CrossRef][Medline]
  12. Kowal RC, Herz J, Goldstein JL, Esser V, Brown MS. 1989 Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins. Proc Natl Acad Sci USA. 86:5810–5814.[Abstract/Free Full Text]
  13. Goldstein JL, Basu SK, Brown MS. 1983 Receptor-mediated endocytosis of low-density lipoprotein in cultured cells. Methods Enzymol. 98:241–260.[Medline]
  14. Rywlin AM, Lopez-Gomez A, Tachmes P, Pardo V. 1971 Ceroid histiocytosis of the spleen in hyperlipemias. Am J Clin Pathol. 56:572–579.[Medline]
  15. Jacobsen CD, Gjone E, Hovig T. 1972 Sea-blue histiocytes in familial lecithin: cholesterol acyltransferase deficiency. Scand J Haematol. 9:106–113.[Medline]
  16. Mahley RW, Innerarity TL, Rall Jr SC, Weisgraber KH, Taylor JM. 1990 Apolipoprotein E: genetic variants provide insights into its structure and function. Curr Opin Lipidol. 1:87–95.
  17. Livak KJ, Hainer JW. 1994 A microtiter plate assay for determining apolipoprotein E genotype and discovery of a rare allele. Hum Mutat. 3:379–385.[CrossRef][Medline]
  18. Ando M, Sasaki J, Hua H, Matsunaga A, Uchida K, Jou K, et al. 1999 A novel 18-amino acid deletion in apolipoprotein E associated with lipoprotein glomerulopathy. Kidney Int. 56:1317–1323.[CrossRef][Medline]
  19. Willnow TE, Sheng Z, Ishibashi S, Herz J. 1994 Inhibition of hepatic chylomicron remnant uptake by gene transfer of a receptor antagonist. Science. 264:1471–1474.[Abstract/Free Full Text]
  20. Herz J, Hamann U, Rogne S, Myklebost O, Gausepohl H, Stanley KK. 1988 Surface location and high affinity for calcium of a 500-kd liver membrane protein closely related to the LDL-receptor suggest a physiological role as lipoprotein receptor. EMBO J. 7:4119–4127.[Medline]
  21. Hussaini IM, Srikumar K, Quesenberry PJ, Gonias SL. 1990 Colony-stimulating factor-1 modulates {alpha}2-macroglobulin receptor expression in murine bone marrow macrophages. J Biol Chem. 265:19441–19446.[Abstract/Free Full Text]
  22. Hussain MM, Mahley RW, Boyles JK, Lindquist PA, Brecht WJ, Innerarity TL. 1989 Chylomicron metabolism. Chylomicron uptake by bone marrow in different animal species. J Biol Chem. 264:17931–17938.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Clin. Chem.Home page
A. R. Rahalkar, J. Wang, S. Sirrs, J. Dimmick, D. Holmes, N. Urquhart, R. A. Hegele, and A. Mattman
An Unusual Case of Severe Hypertriglyceridemia and Splenomegaly
Clin. Chem., March 1, 2008; 54(3): 606 - 610.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nguyen, T. T.
Right arrow Articles by O’Brien, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nguyen, T. T.
Right arrow Articles by O’Brien, T.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals