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ARTICLE |

Genetic Defects in Lipoprotein Metabolism: Title and subTitle BreakElevation of Atherogenic Lipoproteins Caused by Impaired Catabolism FREE

Robert W. Mahley, MD, PhD; Karl H. Weisgraber, PhD; Thomas L. Innerarity, PhD; Stanley C. Rall, Jr, PhD
[+] Author Affiliations

Reprint requests to Gladstone Foundation Laboratories, PO Box 40608, San Francisco, CA 94140 (Dr Mahley).


JAMA. 1991;265(1):78-83. doi:10.1001/jama.1991.03460010078035
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Published online

Certain proteins (called apolipoproteins B and E) on the surface of lipoprotein particles are responsible for mediating the binding of cholesterol-rich particles to specific lipoprotein receptors on the surface of cells and represent a major pathway controlling blood cholesterol levels. Three important disorders of lipoprotein metabolism, which provide insights into the molecular mechanisms responsible for the elevation of specific atherogenic lipoproteins, are the following: (1) Type III hyperlipoproteinemia results from specific mutations in apolipoprotein E that prevent the normal binding of chylomicron remnants and very-lowdensity lipoprotein remnants to lipoprotein receptors. Patients with this disorder who have elevated levels of these remnant lipoproteins develop atherosclerosis. (2) Familial defective apolipoprotein B-100 results from a single amino acid substitution in apolipoprotein B that prevents low-density lipoprotein from binding normally to the low-density lipoprotein receptor and elevates plasma cholesterol levels. (3) Familial hypercholesterolemia, which results in elevated levels of plasma low-density lipoprotein and premature atherosclerosis, is caused by a variety of mutations in the low-density lipoprotein receptor that interfere with the normal binding of lipoproteins to this receptor. These observations not only provide insights into the mechanisms responsible for normal lipoprotein metabolism, but also highlight the potential role of specific lipoproteins in atherogenesis.

(JAMA. 1991;265:78-83)

REFERENCES

 Lowering blood cholesterol to prevent heart disease . JAMA . 1985;;253:2080-2086. Consensus Conference.
The Expert Panel.  Report of the National Cholesterol Education Program Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults . Arch Intern Med. 1988;;48:361-369.
Havel RJ, Goldstein JL, Brown MS.  Lipoproteins and lipid transport . In: Bondy PK, Rosenberg LE, eds. Metabolic Control and Disease . 8th ed. Philadelphia, Pa: WB Saunders Co; 1980;:393-494.
Havel RJ, Kane JP.  Introduction: structure and metabolism of plasma lipoproteins . In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease . 6th ed. New York, NY: McGraw-Hill International Book Co; 1989;:1129-1138.
Mahley RW, Innerarity TL, Rall SC Jr, Weisgraber KH.  Plasma lipoproteins: apolipoprotein structure and function . J Lipid Res. 1984;;25:1277-1294.
Mahley RW.  Atherogenic lipoproteins and coronary artery disease: concepts derived from recent advances in cellular and molecular biology . Circulation . 1985;;72:943-948.
Brown MS, Goldstein JL.  A receptor-mediated pathway for cholesterol homeostasis . Science . 1986;;232:34-47.
Mahley RW, Innerarity TL.  Lipoprotein receptors and cholesterol homeostasis . Biochim Biophys Acta . 1983;;737:197-222.
Mahley RW.  Apolipoprotein E: cholesterol transport protein with expanding role in cell biology . Science . 1988;;240:622-630.
Wardell MR, Brennan SO, Janus ED, Fraser R, Carrell RW.  Apolipoprotein E2-Christchurch (136 Arg Ser): new variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia . J Clin Invest. 1987;;80:483-490.
Havel RJ, Kotite L, Kane JP, Tun P, Bersot T.  Atypical familial dysbetalipoproteinemia associated with apolipoprotein phenotype E3/3 . J Clin Invest. 1983;;72:379-387.
Rall SC Jr, Newhouse YM, Clarke HRG, et al.  Type III hyperlipoproteinemia associated with apolipoprotein E phenotype E3/3: structure and genetics of an apolipoprotein E3 variant . J Clin Invest. 1989;;83:1095-1101.
Rall SC Jr, Weisgraber KH, Innerarity TL, Mahley RW.  Structural basis for receptor binding heterogeneity of apolipoprotein E from type III hyperlipoproteinemic subjects . Proc Natl Acad Sci U S A. 1982;;79:4696-4700.
Rall SC Jr, Weisgraber KH, Innerarity TL, Bersot TP, Mahley RW, Blum CB.  Identification of a new structural variant of human apolipoprotein E, E2 (Lys146→Gln), in a type III hyperlipoproteinemic subject with the E3/2 phenotype . J Clin Invest. 1983;;72:1288-1297.
Mann WA, Gregg RE, Sprecher DL, Brewer HB Jr.  Apolipoprotein E-1Harrisburg: a new variant of apolipoprotein E dominantly associated with type III hyperlipoproteinemia . Biochim Biophys Acta . 1989;;1005:239-244.
Havekes L, de Wit E, Gevers Leuven J, et al.  Apolipoprotein E3-Leiden: a new variant of human apolipoprotein E associated with familial type III hyperlipoproteinemia . Hum Genet. 1986;;73:157-163.
Wardell MR, Weisgraber KH, Havekes LM, Rall SC Jr.  Apolipoprotein E3-Leiden contains a seven-amino acid insertion that is a tandem repeat of residues 121 to 127 . J Biol Chem. 1989;; 264:21205-21210.
Innerarity TL, Friedlander EJ, Rall SC Jr, Weisgraber KH, Mahley RW.  The receptor-binding domain of human apolipoprotein E: binding of apolipoprotein E fragments . J Biol Chem. 1983;; 258:12 341-12 347.
Weisgraber KH, Innerarity TL, Harder KJ, et al.  The receptor-binding domain of human apolipoprotein E: monoclonal antibody inhibition of binding . J Biol Chem. 1983;;258:12 348-12 354.
Lalazar A, Weisgraber KH, Rall SC Jr, et al.  Site-specific mutagenesis of human apolipoprotein E: receptor binding activity of variants with single amino acid substitutions . J Biol Chem. 1988;; 263:3542-3545.
Mahley RW, Innerarity TL, Weisgraber KH, et al.  Cellular and molecular biology of lipoprotein metabolism: characterization of lipoprotein receptor-ligand interactions . Cold Spring Harb Symp Quant Biol. 1986;;51:821-828.
Innerarity TL, Weisgraber KH, Arnold KS, Rall SC Jr, Mahley RW.  Normalization of receptor binding of apolipoprotein E2: evidence for modulation of the binding site conformation . J Biol Chem. 1984;;259:7261-7267.
Chen S-H, Yang C-Y, Chen P-F, et al.  The complete cDNA and amino acid sequence of human apolipoprotein B-100 . J Biol Chem. 1986;; 261:12 918-12 921.
Cladaras C, Hadzopoulou-Cladaras M, Nolte RT, Atkinson D, Zannis VI.  The complete sequence and structural analysis of human apolipoprotein B-100: relationship between apo B-100 and apo B-48 forms . EMBO J. 1986;;5:3495-3507.
Knott TJ, Pease RJ, Powell LM, et al.  Complete protein sequence and identification of structural domains of human apolipoprotein B . Nature . 1986;;323:734-738.
Law SW, Grant SM, Higuchi K, et al.  Human liver apolipoprotein B-100 cDNA: complete nucleic acid and derived amino acid sequence . Proc Natl Acad Sci U S A. 1986;;83:8142-8146.
Pease RJ, Milne RW, Jessup WK, et al.  Use of bacterial expression cloning to localize the epitopes for a series of monoclonal antibodies against apolipoprotein B-100 . J Biol Chem. 1990;;265:553-568.
Milne R, Theolis R Jr, Maurice R, et al.  The use of monoclonal antibodies to localize the low-density lipoprotein receptor-binding domain of apolipoprotein B . J Biol Chem. 1989;;264:19 754-19 760.
Mahley RW, Innerarity TL, Rall SC Jr, Weisgraber KH.  Lipoproteins of special significance in atherosclerosis: insights provided by studies of type III hyperlipoproteinemia . Ann N Y Acad Sci. 1985;;454:209-221.
Mahley RW, Rall SC Jr.  Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism . In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease . 6th ed. New York, NY: McGraw-Hill International Book Co; 1989;:1195-1213.
Breslow JL.  Genetic basis of lipoprotein disorders . J Clin Invest. 1989;;84:373-380.
Innerarity TL, Hui DY, Bersot TP, Mahley RW.  Type III hyperlipoproteinemia: a focus on lipoprotein receptor-apolipoprotein E2 interactions . In: Angel A, Frohlich J, eds. Lipoprotein Deficiency Syndromes . New York, NY: Plenum Publishing Corp; 1986;:273-288.
Mahley RW, Innerarity TL, Rall SC Jr, Weisgraber KH, Taylor JM.  Apolipoprotein E: genetic variants provide insights into its structure and function . Curr Opin Lipidol. 1990;;1:87-95.
Ehnholm C, Mahley RW, Chappell DA, Weisgraber KH, Ludwig E, Witztum JL.  Role of apolipoprotein E in the lipolytic conversion of β-very low density lipoproteins to low density lipoproteins in type III hyperlipoproteinemia . Proc Natl Acad Sci U S A. 1984;;81:5566-5570.
Brown MS, Goldstein JL.  Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis . Annu Rev Biochem. 1983;;52:223-261.
Steinberg D.  Lipoproteins and atherosclerosis: a look back and a look ahead . Arteriosclerosis . 1983;;3:283-301.
Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL.  Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity . N Engl J Med. 1989;;320:915-924.
Koo C, Wernette-Hammond ME, Innerarity TL.  Uptake of canine β-very low density lipoproteins by mouse peritoneal macrophages is mediated by a low density lipoprotein receptor . J Biol Chem. 1986;;261:11 194-11 201.
Pitas RE, Innerarity TL, Mahley RW.  Foam cells in explants of atherosclerotic rabbit aortas have receptors for β-very low density lipoproteins and modified low density lipoproteins . Arteriosclerosis . 1983;;3:2-12.
Brown MS, Goldstein JL.  How LDL receptors influence cholesterol and atherosclerosis . Sci Am. 1984;;251:58-66.
Mahley RW, Hui DY, Innerarity TL, Beisiegel U.  Chylomicron remnant metabolism: role of hepatic lipoprotein receptors in mediating uptake . Arteriosclerosis . 1989;;9( (suppl 1) ):I-14-I-18.
Goldstein JL, Brown MS.  Familial hypercholesterolemia . In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease . 6th ed. New York, NY: McGraw-Hill International Book Co; 1989;:1215-1250.
Innerarity TL, Weisgraber KH, Arnold KS, et al.  Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding . Proc Natl Acad Sci U S A. 1987;;84:6919-6923.
Weisgraber KH, Innerarity TL, Newhouse YM, et al.  Familial defective apolipoprotein B-100: enhanced binding of monoclonal antibody MB47 to abnormal low density lipoproteins . Proc Natl Acad Sci U S A. 1988;;85:9758-9762.
Soria LF, Ludwig EH, Clarke HRG, Vega GL, Grundy SM, McCarthy BJ.  Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100 . Proc Natl Acad Sci U S A. 1989;;86:587-591.
Innerarity TL, Mahley RW, Weisgraber KH, et al.  Familial defective apolipoprotein B100: a mutation of apolipoprotein B that causes hypercholesterolemia . J Lipid Res. 1990;;1:1337-1349.
Tybjaerg-Hansen A, Gallagher J, Vincent J, et al.  Familial defective apolipoprotein B-100: detection in the United Kingdom and Scandinavia, and clinical characteristics of 10 cases . Atherosclerosis . 1990;;80:235-242.
Schuster H, Rauh G, Kormann B, et al.  Familial defective apolipoprotein B-100: comparison with familial hypercholesterolemia in 18 cases detected in Munich . Arteriosclerosis . 1990;;10:577-581.
Pitas RE.  Expression of the acetyl low-density lipoprotein receptor by rabbit fibroblasts and smooth muscle cells: up-regulation by phorbol esters . J Biol Chem. 1990;;65:12 722-12 727.

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 Lowering blood cholesterol to prevent heart disease . JAMA . 1985;;253:2080-2086. Consensus Conference.
The Expert Panel.  Report of the National Cholesterol Education Program Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults . Arch Intern Med. 1988;;48:361-369.
Havel RJ, Goldstein JL, Brown MS.  Lipoproteins and lipid transport . In: Bondy PK, Rosenberg LE, eds. Metabolic Control and Disease . 8th ed. Philadelphia, Pa: WB Saunders Co; 1980;:393-494.
Havel RJ, Kane JP.  Introduction: structure and metabolism of plasma lipoproteins . In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease . 6th ed. New York, NY: McGraw-Hill International Book Co; 1989;:1129-1138.
Mahley RW, Innerarity TL, Rall SC Jr, Weisgraber KH.  Plasma lipoproteins: apolipoprotein structure and function . J Lipid Res. 1984;;25:1277-1294.
Mahley RW.  Atherogenic lipoproteins and coronary artery disease: concepts derived from recent advances in cellular and molecular biology . Circulation . 1985;;72:943-948.
Brown MS, Goldstein JL.  A receptor-mediated pathway for cholesterol homeostasis . Science . 1986;;232:34-47.
Mahley RW, Innerarity TL.  Lipoprotein receptors and cholesterol homeostasis . Biochim Biophys Acta . 1983;;737:197-222.
Mahley RW.  Apolipoprotein E: cholesterol transport protein with expanding role in cell biology . Science . 1988;;240:622-630.
Wardell MR, Brennan SO, Janus ED, Fraser R, Carrell RW.  Apolipoprotein E2-Christchurch (136 Arg Ser): new variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia . J Clin Invest. 1987;;80:483-490.
Havel RJ, Kotite L, Kane JP, Tun P, Bersot T.  Atypical familial dysbetalipoproteinemia associated with apolipoprotein phenotype E3/3 . J Clin Invest. 1983;;72:379-387.
Rall SC Jr, Newhouse YM, Clarke HRG, et al.  Type III hyperlipoproteinemia associated with apolipoprotein E phenotype E3/3: structure and genetics of an apolipoprotein E3 variant . J Clin Invest. 1989;;83:1095-1101.
Rall SC Jr, Weisgraber KH, Innerarity TL, Mahley RW.  Structural basis for receptor binding heterogeneity of apolipoprotein E from type III hyperlipoproteinemic subjects . Proc Natl Acad Sci U S A. 1982;;79:4696-4700.
Rall SC Jr, Weisgraber KH, Innerarity TL, Bersot TP, Mahley RW, Blum CB.  Identification of a new structural variant of human apolipoprotein E, E2 (Lys146→Gln), in a type III hyperlipoproteinemic subject with the E3/2 phenotype . J Clin Invest. 1983;;72:1288-1297.
Mann WA, Gregg RE, Sprecher DL, Brewer HB Jr.  Apolipoprotein E-1Harrisburg: a new variant of apolipoprotein E dominantly associated with type III hyperlipoproteinemia . Biochim Biophys Acta . 1989;;1005:239-244.
Havekes L, de Wit E, Gevers Leuven J, et al.  Apolipoprotein E3-Leiden: a new variant of human apolipoprotein E associated with familial type III hyperlipoproteinemia . Hum Genet. 1986;;73:157-163.
Wardell MR, Weisgraber KH, Havekes LM, Rall SC Jr.  Apolipoprotein E3-Leiden contains a seven-amino acid insertion that is a tandem repeat of residues 121 to 127 . J Biol Chem. 1989;; 264:21205-21210.
Innerarity TL, Friedlander EJ, Rall SC Jr, Weisgraber KH, Mahley RW.  The receptor-binding domain of human apolipoprotein E: binding of apolipoprotein E fragments . J Biol Chem. 1983;; 258:12 341-12 347.
Weisgraber KH, Innerarity TL, Harder KJ, et al.  The receptor-binding domain of human apolipoprotein E: monoclonal antibody inhibition of binding . J Biol Chem. 1983;;258:12 348-12 354.
Lalazar A, Weisgraber KH, Rall SC Jr, et al.  Site-specific mutagenesis of human apolipoprotein E: receptor binding activity of variants with single amino acid substitutions . J Biol Chem. 1988;; 263:3542-3545.
Mahley RW, Innerarity TL, Weisgraber KH, et al.  Cellular and molecular biology of lipoprotein metabolism: characterization of lipoprotein receptor-ligand interactions . Cold Spring Harb Symp Quant Biol. 1986;;51:821-828.
Innerarity TL, Weisgraber KH, Arnold KS, Rall SC Jr, Mahley RW.  Normalization of receptor binding of apolipoprotein E2: evidence for modulation of the binding site conformation . J Biol Chem. 1984;;259:7261-7267.
Chen S-H, Yang C-Y, Chen P-F, et al.  The complete cDNA and amino acid sequence of human apolipoprotein B-100 . J Biol Chem. 1986;; 261:12 918-12 921.
Cladaras C, Hadzopoulou-Cladaras M, Nolte RT, Atkinson D, Zannis VI.  The complete sequence and structural analysis of human apolipoprotein B-100: relationship between apo B-100 and apo B-48 forms . EMBO J. 1986;;5:3495-3507.
Knott TJ, Pease RJ, Powell LM, et al.  Complete protein sequence and identification of structural domains of human apolipoprotein B . Nature . 1986;;323:734-738.
Law SW, Grant SM, Higuchi K, et al.  Human liver apolipoprotein B-100 cDNA: complete nucleic acid and derived amino acid sequence . Proc Natl Acad Sci U S A. 1986;;83:8142-8146.
Pease RJ, Milne RW, Jessup WK, et al.  Use of bacterial expression cloning to localize the epitopes for a series of monoclonal antibodies against apolipoprotein B-100 . J Biol Chem. 1990;;265:553-568.
Milne R, Theolis R Jr, Maurice R, et al.  The use of monoclonal antibodies to localize the low-density lipoprotein receptor-binding domain of apolipoprotein B . J Biol Chem. 1989;;264:19 754-19 760.
Mahley RW, Innerarity TL, Rall SC Jr, Weisgraber KH.  Lipoproteins of special significance in atherosclerosis: insights provided by studies of type III hyperlipoproteinemia . Ann N Y Acad Sci. 1985;;454:209-221.
Mahley RW, Rall SC Jr.  Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism . In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease . 6th ed. New York, NY: McGraw-Hill International Book Co; 1989;:1195-1213.
Breslow JL.  Genetic basis of lipoprotein disorders . J Clin Invest. 1989;;84:373-380.
Innerarity TL, Hui DY, Bersot TP, Mahley RW.  Type III hyperlipoproteinemia: a focus on lipoprotein receptor-apolipoprotein E2 interactions . In: Angel A, Frohlich J, eds. Lipoprotein Deficiency Syndromes . New York, NY: Plenum Publishing Corp; 1986;:273-288.
Mahley RW, Innerarity TL, Rall SC Jr, Weisgraber KH, Taylor JM.  Apolipoprotein E: genetic variants provide insights into its structure and function . Curr Opin Lipidol. 1990;;1:87-95.
Ehnholm C, Mahley RW, Chappell DA, Weisgraber KH, Ludwig E, Witztum JL.  Role of apolipoprotein E in the lipolytic conversion of β-very low density lipoproteins to low density lipoproteins in type III hyperlipoproteinemia . Proc Natl Acad Sci U S A. 1984;;81:5566-5570.
Brown MS, Goldstein JL.  Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis . Annu Rev Biochem. 1983;;52:223-261.
Steinberg D.  Lipoproteins and atherosclerosis: a look back and a look ahead . Arteriosclerosis . 1983;;3:283-301.
Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL.  Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity . N Engl J Med. 1989;;320:915-924.
Koo C, Wernette-Hammond ME, Innerarity TL.  Uptake of canine β-very low density lipoproteins by mouse peritoneal macrophages is mediated by a low density lipoprotein receptor . J Biol Chem. 1986;;261:11 194-11 201.
Pitas RE, Innerarity TL, Mahley RW.  Foam cells in explants of atherosclerotic rabbit aortas have receptors for β-very low density lipoproteins and modified low density lipoproteins . Arteriosclerosis . 1983;;3:2-12.
Brown MS, Goldstein JL.  How LDL receptors influence cholesterol and atherosclerosis . Sci Am. 1984;;251:58-66.
Mahley RW, Hui DY, Innerarity TL, Beisiegel U.  Chylomicron remnant metabolism: role of hepatic lipoprotein receptors in mediating uptake . Arteriosclerosis . 1989;;9( (suppl 1) ):I-14-I-18.
Goldstein JL, Brown MS.  Familial hypercholesterolemia . In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease . 6th ed. New York, NY: McGraw-Hill International Book Co; 1989;:1215-1250.
Innerarity TL, Weisgraber KH, Arnold KS, et al.  Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding . Proc Natl Acad Sci U S A. 1987;;84:6919-6923.
Weisgraber KH, Innerarity TL, Newhouse YM, et al.  Familial defective apolipoprotein B-100: enhanced binding of monoclonal antibody MB47 to abnormal low density lipoproteins . Proc Natl Acad Sci U S A. 1988;;85:9758-9762.
Soria LF, Ludwig EH, Clarke HRG, Vega GL, Grundy SM, McCarthy BJ.  Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100 . Proc Natl Acad Sci U S A. 1989;;86:587-591.
Innerarity TL, Mahley RW, Weisgraber KH, et al.  Familial defective apolipoprotein B100: a mutation of apolipoprotein B that causes hypercholesterolemia . J Lipid Res. 1990;;1:1337-1349.
Tybjaerg-Hansen A, Gallagher J, Vincent J, et al.  Familial defective apolipoprotein B-100: detection in the United Kingdom and Scandinavia, and clinical characteristics of 10 cases . Atherosclerosis . 1990;;80:235-242.
Schuster H, Rauh G, Kormann B, et al.  Familial defective apolipoprotein B-100: comparison with familial hypercholesterolemia in 18 cases detected in Munich . Arteriosclerosis . 1990;;10:577-581.
Pitas RE.  Expression of the acetyl low-density lipoprotein receptor by rabbit fibroblasts and smooth muscle cells: up-regulation by phorbol esters . J Biol Chem. 1990;;65:12 722-12 727.
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