Physiological

Reviews

Published and Copyright by The American Physiological Society

Lipoprotein RICHARD Baylor

Vol. 56, No. 2, April

Structure L. JACKSON, ANTONIO

ColZege of Medicine

and Metabolism

JOEL D. MORRISETT, M. GOTTO, JR.

and The Methodist

Hospital,

AND

Houston., Texas 77030

I. Introduction ........................................................... A. Historical .......................................................... B. Nomenclature ....................................................... II. Lipoprotein Composition ................................................ A. Chylomicrons ....................................................... ........................................ B. Very-low-density lipoproteins C. Low-density lipoproteins ............................................. ............................................ D. High-density lipoproteins E. Lipoprotein (a) ....................................................... F. Lipoprotein-X ....................................................... III. Apoprotein Structure and Function ...................................... A. ApoC ............................................................... B. ApoB ............................................................... C. ApoA .............................................................. D. Thin-line protein .................................................... E. Arginine-rich protein ................................................ IV. Models of Lipoprotein Structure ......................................... A. Lipid-core model .................................................... B. LDL models ........................................................ C. HDL models . ............................. .......................... V. Lipoprotein Metabolism ................................................. A. Synthesis ........................................................... B. Catabolism ......................................................... VI. Conclusion .............................................................

I.

1976

259 259 261 262 262 262 263 264 264 265 265 265 267 267 270 270 271 271 271 272 276 276 287 299

INTRODUCTION

A. Historical

In 1929, Macheboeuf (318, 319) described the preparation from horse serum of a fraction that contained lipid associated with protein. This material was called the “coenapse precipitated by acid.” Subsequently, the lipidprotein complex became known as a lipoprotein. Interest in this class of 259

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serum proteins increased in the 1950’swhen ultracentrifugal (175) and paper electrophoretic (96) procedures became available for their isolation and characterization. At the same time, Gofman and his co11 .eagues (174) called attention to the relationshi p between elevated 1evels of plasma lipoproteins and the occurrence of premature coronary artery disease; their review on this subject appeared in Physiologic& Reviews over 20 years ago (1974). Other studies in the 1950’s also suggested a relationship between blood lipids and coronary heart disease. Based largely on epidemiological data, Keys et al. (265, 266) suggested that the dietary intake of saturated fat influenced the level of blood cholesterol. Kinsell et al. (272) confirmed this proposal experimentally by demonstrating that dietary unsaturated fats lowered blood cholesterol. Ahrens et al. (6) described in 1957an effect of saturated fats on serum cholesterol concentrations. Ahrens et al. (5) further reported in 1961 that certain subjects with hyperlipidemia were sensitive to dietary carbohydrate, whereas others were sensitive to dietary fat. An important publication by Reviews and Fredrickson and Gordon (148) appeared in 1958in Physiological summarized the structural information concerning the plasma lipoproteins and their relati .onship to pl asm.a lipid transport. It was pointed out that all plas#ma li .pids, other than the free fatty acids, are transported as part of macromolecular complexes called lipoproteins. Based on end-group analyses, there was evidence for at least three different apolipoproteins. Interest in the lipoproteins as they relate to hyperlipidemia burgeoned in the 1960’s. This resulted in part from new technical advances in the use of paper electrophoresis for the separation of lipoprotein classes (300). In 1967, Fredrickson et al. (151) published a comprehensive survey of the structural physiological knowledge about the plasma lipoproteins and suggested a method for defining hyperlipoproteinemia on the basis of five phenotypes. The use of plasma lipoprotein phenotyping became so widespread that a dc0 ument describing the definition of the vari ous patterns was prepared by the World Health Organization (43). However, in recent years, i t has become evident th .at the identific atio n of a phenoty Pe d.oes not necessarily define a genotype. Goldstein and co-workers (183, 184, 220) h ave described three different, apparently dominant, genetic traits in the relatives of survivors of myocardial infarction and have referred to these inherited disorders as familial hypercholesterolemia, familial hypertriglyceridemia, and familial combined hyperlipidemia. In these studies, none of the genetic disorders was specified by a single lipoprotein pattern. In this review, we emphasize recent investigations concerning the structure and metabolism of the plasma lipoproteins and, when appropriate, their relationship to parti .cular patholo gic disorders. M uch of the inform .ation presented here concerns the human plasma lipoproteins. However, we discuss, to a limited extent, nonhuman lipoproteins, especially where the information may be of some relevance to man. The reader is also referred to other reviews (115, 146, 152, 304, 343, 429, 442, 443, 452), to books (349, 511), and to symposia (145, 430).

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261

METABOLISM

B. Nomenclature

The classification and nomenclature of the plasma lipoproteins have been based primarily on operational definitions as determined by their electrophoretie mobility or by their rate of ultracentrifugal flotation in salt solutions (481). Based on these criteria, human plasma lipoproteins from normal subjects have been divided traditionally into five classes:chylomicrons, very-lowdensity lipoproteins (VLDL), low-density lipoproteins (LDL), high-density lipoproteins (HDL), and very-high-density lipoproteins (VHDL). A summary of the propertics of these classes is given in Table 1. Although the use of the five-class system for describing the plasma lipoproteins is convenient, there are a number of clinical conditions for which this classification is not suficient, e.g., the lipoprotein patterns in obstructive liver disease, type III dyslipoproteinemia, abetalipoproteinemia, Tangier disease, and lecithin:cholesterol acyltransferase deficiency, all of which are discussed later in this review. Each lipoprotein class is heterogeneous with respect to its protein constituents. At present, there is no universally accepted system of nomenclature of the lipoprotein proteins (apoproteins). Alaupovic and co-workers (7, 8, 202) have proposed a nomenclature based on the premise that there are certain apoproteins that define individual lipoprotein families. In this system, the families are designated A, B, and C. ApoA refers to the apoproteins that are primarily, but not exclusively, found in HDL. ApoB is the major apoprotein of LDL, but also comprises about 35% of the protein of VLDL. ApoC represents a TABLE

I. Composition

and properties

- of human

plasma

lipoproteins

-T-

Properties Density,

1 %!Fi-

g/ml

Electrophoreti mobility

c 1 Origin

VLDL

LDL

HDL

VHDL

0.95-1.006

1.006-1.063

1.063-1.210

1.210-1.250

Prebeta

Beta

Alpha

Alpha

ApoB

ApoA-I ApoA-II

ApoA-I ApoA-II

Major

apoproteins

ApoB ApoC-I ApoC- II ApoC-III

ApoB ApoC-I ApoC-II ApoC-III Arginine-rich protein

Minor

apoproteins

ApoA-I ApoA-II

Thin-line tein ApoA-I ApoA-II

pro-

ApoC-I ApoC-II ApoC-III Thin-line protein Arginine-rich protein

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group of proteins originally described in VLDL but which are also present in HDL. Other investigators have used the COOH-terminal amino acid as a way of designating the apoprotein (152, 468). Scanu et al. (441) have used a nomenclature based on chromatographic separation, e.g., fractions III, IV, and V. For the present review, we have adopted the A, B, C terminology of Alaupovic (7, 8) to designate the individual apoproteins. Since there is disagreement concerning the designation of apoD and apoE, we have retained the trivial names of “thin-line” protein and “arginine-rich” protein, respectively. Other apoproteins have also been described, e.g., a “glycine-rich” or “highly polar” protein (466). Although we have used the A, B, C designation, it is not meant to imply the occurrence of discrete lipoprotein families containing only apoA, apoB, and apoC, a subject still under active investigation. II.

LIPOPROTEIN

A.

Chylomicrons

COMPOSITION

Most dietary triglycerides are transported in the plasma as chylomicrons (103, 538). Triglycerides are hydrolyzed in the duodenum to free fatty acids and 2-monoglycerides; after absorption, triglycerides are resynthesized and are incorporated into a chylomicron particle in the intestinal wall. Fatty acids containing 10 carbons or less are absorbed directly into the portal blood. Chylomicrons are transported by the lymphatic system to the thoracic duct, where they enter the systemic circulation. Chylomicrons isolated from lymph contain less protein and more phospholipid than those isolated from plasma (56). Lymph chylomicrons are of heterogeneous size ranging in diameter from 300 to 5000 A. They contain mainly triglyceride and there is a direct relationship between the size of the chylomicron particle and its triglyceride content. Chylomicrons also contain by weight a small fraction of phospholipid (8%) and cholesterol (5%). Phosphatidylcholine and sphingomyelin are the major phospholipid components (481). The protein content of lymph chylomicrons is small and variable. Kostner and Holasek (276, 280) found that human lymph chylomicrons isolated from the thoracic duct contain all the apoproteins of VLDL, the approximate composition being 66% apoC, 22% apoB, and 12% apoA. An interesting point of this study is that apoA-I and apoA-II were present in approximately equal quantities by weight, which differs from the ratio of 3:l found in human plasma HDL (429). Glickman and Kirsch (167) showed that the larger chylomicron particles contain a greater proportion of apoB than the smaller ones. Furthermore, intestinal chylomicrons gained apoC and lost apoB when incubated with serum. B. Very-Low-Density

Lipoproteins

In man, the VLDL particle is the major transport vehicle for endogeneously synthesized triglyceride (481). The VLDL particles span a spectrum

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of sizes from 280 to 750 A and are heterogeneous by several techniques, e.g., by ultracentrifugation (215, 307, 311), by chromatography on agarose (328, 388, 420, 421) or on concanavalin A bound to Sepharose (334, 469), by isoelectric focusing (374), and by affinity chromatography with antiserum to VLDL covalently bound to Sepharose (375). The size of the VLDL particle is related directly to the triglyceride content and inversely to the phospholipid and protein. The composition of VLDL by weight is 8-10% protein and 90-92% lipid (481). Of the lipids, triglyceride is the most abundant component (56%); the average content of phospholipid is 19-210/cand of cholesterol, 17%. The esterified:unesterifed cholesterol ratio in VLDL is approximately 1. Phosphatidylcholine and sphingomyelin are the predominant phospholipids. The VLDL are also heterogeneous with respect to apoprotein composition, differing from one subfraction to the next (114, 469). In the presence of detergent, e.g., sodium decyl sulfate, the lipid-free VLDL (apoVLDL) can be solubilized and fractionated on Sephadex G-100 (80, 186). The protein eluting at the void volume has physicochemical and immunological properties identical to the major apoprotein of LDL, apoB (186). By gravimetric measurements, apoB accounts for approximately 35% of the total VLDL protein (80). However, by quantitative radioimmunoassay, apoB accounts for only 20-30% of the total protein (446, 448). The retarded fraction from Sephadex G-100 contains the “arginine-rich” protein and apoC. The latter can be fractionated by chromatography on DEAE-cellulose (79,469) or by isoelectric focusing (15). The relative abundance of each apoC protein varies with the individual, with the degree of hyperlipidemia, and with age (469). The larger the VLDL particle, the greater is its relative content of apoC and the lower is its content of apoB (114). By immunochemical methods, VLDL may also be shown to contain apoA (282). Quantitative measurements indicate the apoVLDL contains less than 1% apoA (258). C. Low-Density Lipoproteins The average concentration of LDL in fasting normal adult American males is 400 mg/lOO ml and in femaies is 340 mg/lOO ml (481). The LDL contains approximately 75% lipid and 25% protein (481). Its composition by weight is 50% cholesteryl esters, 30% phospholipids, 10% unesterified cholesterol, and 10% triglycerides. Phosphatidylcholine and sphingomyelin account, respectively, for 65% and 25% of the total phospholipids. Linoleic acid is the major fatty acid in the LDL lipids. The LDL particles appear almost spherical and are quite uniform in size as viewed by electron microscopy after negative staining (139); 80% of the particles are between 210 and 250 A in diameter. Reported molecular weights for LDL vary from about 2-3.5 x 10” (2, 133, 134, 308). Subfractions of LDL have been isolated between d 1.019 and 1.063 (132, 212, 308, 451). Although the molecular weights of these subfractions are different, each LDL particle contains a constant quantity of protein amounting to about 510,000 daltons/ particle. The major apoprotein(s) present in LDL is apoB. By specific radioim-

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munoassay, its mean concentration in the plasma of healthy subjects is 90 t ml (42). Lee and Alaupovic (296-298) have also reported small quantities of apoC and apoA in LDL. ApoC was found mainly between d 1.006 and 1.019 and the apoA between d 1.050 and 1.063. In addition, Kostner (275) has isolated a lipoprotein particle in the HDL density range d 1.0731.125 that contains only apoB. This lipoprotein has been purified by immunoabsorption and is referred to as LpBljD1,. Low-density lipoproteins have also been isolated from a number of nonhuman sources, including the rat (53, 273), chicken (229), pig (250), whale (384), and primates (135, 299).

24 mg/lOO

D. High-Density

Lipoproteins

The HDL are the smallest of the lipoprotein particles, having diameters of 90-120 A (139). A minor HDL component, HDL,, has been isolated between d 1.050 and 1.063 (13) and has been shown to have electrophoretic and immunochemical properties similar to HDL,. The HDL have been fractionated into several subspecies by differential (85) and rate-zonal ultracentrifugation (373) and by analytical and preparative gel electrofocusing (320, 407, 502, 503). The physiologic significance of these subspecies is unknown. It is known, however, that the human plasma HDL,:HDL:, ratio is affected by various physiologic and pathologic parameters. Premenopausal women contain about 3 times as much HDL., as men, suggesting a relationship between HDL., and estrogen levels (119, Z-79). Lipids account for about one-half of HDL by weight. Phospholipids (4251%), cholesterol (32%), and triglycerides (10%) are the main components (481). Phosphatidylcholine constitutes 70- 80% of the total phospholipids and sphingomyelin 12-14%; phosphatidylserine and phosphatidylinositol are minor constituents. Linoleic acid is the predominant fatty acid of the cholesteryl esters. The protein moieties of HDL may be isolated by chromatography of apoHDL on DEAE-cellulose (466) or Sephadex G-200 (441) to yield two major components, both having COOH-terminal glutamine. In this review, these two apoproteins are designated as apoA-I and apo-II. The ratio of apoA-I to apoA-II varies within each HDL subfraction. According to Kostner et al. (282) and Borut and Aladjem (65), the ratio of apoA-I to apoA-II is greater in HDL, than in HDL:,. In addition to these two major proteins, HDL also contains as minor constituents the apoC proteins, the “thin-line” protein, and the “arginine-rich” protein. E. Lipoprotein

(a)

Although it exhibits many of the properties of LDL (49, 50), Lp(a) should be considered as an additional lipoprotein class. Lp(a) can be isolated from plasma between d 1.050 and 1.120, has a molecular weight of about 5 x lo’;, and exhibits pre-P-mobility on agarose electrophoresis (111, 475). Although the lipid compositions of LDL and Lp(a) are similar, their protein components

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are quite different. Lp(a), when delipidated, contains 65% apoB, 15% albumin, and a unique apoprotein called apoLp(a) (110, 513). In early studies (50), the frequency of occurrence of Lp(a) in a general population was about 35%. However, with the use of more sensitive radial immunodiffusion techniques (14) or “rocket” electrophoresis (522), Lp(a) has been shown in 75-78% of two randomly selected populations. In the American population, Lp(a) was present at an average concentration of 14 mg/lOO ml. Its concentration does not correlate well with age, sex, lipid concentrations, or with occurrence of coronary artery disease (14, 51, 522). Albers et al. (16) have suggested that Lp(a) concentration is determined by polygenic inheritance. The functional significance of Lp(a) is unknown. Its occurrence in nonhuman species has not yet been described. F. Lipoprotein-X

Patients with biliary obstruction or with 1ecithin:cholesterol acyltransferase (LCAT) deficiency (sect. v, B4) have an abnormal lipoprotein called Lp-X that contains a high proportion of phospholipid and unesterified cholesterol (459, 460, 505). The LCAT deficiency cannot account for the occurrence of Lp-X in all subjects with biliary obstruction (263, 403, 523, 524). Lp-X may be separated from LDL by zonal centrifugation or by hydroxyapatite chromatography (97) and may be quantitated by electrophoresis in agar (402). Negatively stained preparations of Lp-X form rouleaux structures when examined by electron microscopy (210,458, 515). Chemical modification by succinylation does not alter the rouleaux structures (255). Seidel et al. (461) have claimed that Lp-X lacks apoA and have suggested that the abnormal lipoprotein in these subjects is the result of synthesis of an altered apoA that does not bind lipid. Recently, Muller et al. (346) isolated a triglyceride-rich LDL from the plasma of cholestatic patients, who had markedly reduced hepatic lipase activity. These authors reason that the abnormal lipoprotein particles isolated (300-700 A in diameter) represented an intermediate in chylomicron catabolism. III.

APOPROTEIN

STRUCTURE

AND

FUNCTION

Much of the detailed information on the chemical and physical properties of the individual apoproteins has been described in a recent review by Morrisett et al. (343). Therefore, only a brief summary of the apoproteins is discussed here. The amino acid sequence of apoC-I (Fig. l), apoC-III (Fig. 2), apoA-I (Fig. 3>, and apoA-II (Fig. 4) has been determined. A. ApoC

ApoC-I is a single polypeptide chain of 57 amino acid residues (Fig. 1) with COOH-terminal serine (248, 472). An earlier report (79) of valine as the

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COOH terminus has now been corrected (225,336). In addition to binding and transporting lipid (138, 24’7), Soutar et al. (487) have reported that apoC-I activates plasma LCAT. Ganesan et al. (157, 158) have also shown that this protein activates lipoprotein lipase purified from human postheparin plasma; the latter observation remains to be confirmed. ApoC-II is a protein of about 100 amino acid residues (81). Its amino acid sequence has not yet been reported. As indicated by ultracentrifugation in the presence of guanidine hydrochloride, apoC-II has a molecular weight of approximately 12,500 (81). In addition to binding lipid (138), apoC-II has been shown to be a potent activator of lipoprotein lipase from both human and rat postheparin plasma and from cows’ milk (55,215,218,293). The role of apoC-II in lipoprotein metabolism is discussed in section v, B5. ApoC-III is a single polypeptide chain (Fig. 2) of 79 amino acid residues (70, 471). A carbohydrate moiety is attached to threonine-74 by an O-glycosidic linkage. The polysaccharide contains 1 mol of galactose and galactosamine, and either 0, 1, or 2 mol of sialic acid/m01 of polypeptide (70, 81); the polymorphism of apoC-III on polyacrylamide-gel electrophoresis is due to NH*-Thr-Pro-Asp-Val-Ser-Ser 5

qbAla-Leu-Asp-Lys-Leu-Lys-Glu-Phe

Leu-Glu-Asp-Lys-Ala-Arg-Glu-Leu-Ile-Ser-Arg-lle 25 20

35

,

I Gly-Asn-Thr-

l

10

15

l

- Lys-Gln-Ser,30

40

45

50

4

Lys-lie-Asp-Ser-COOH 55 FIG. 1. Amino acid sequence of human plasma very-low-density apolipoprotein apoC-I (apoLP-Ser) as described by Jackson et al. (248) and Shulman et al. (472). Encircled amino acids are in those regions that contain amphipathic helical structure as described in text and Fig. 7. H~N-Ser-GIu-Ala-Glu-Asp-Ala-Ser-Leu-Leu-Ser-Phe-Met-Gln-Gly-Tyr-Met-Lys-Hts-Ala-Thr-Lys-Thr-Ala-Lys-Asp-Ala-Leu1 5 10 15 20

Ser-Ser-Val-Gln-Ser-Gln-Gln-Val-Ala-Ala-Gln-Gln-Arg~ 35 30

Ser -Thr-Val-Lys-Asp-Lys55

40

Phe -Ser-Glu-Phe-Trp-Asp 60

65

Gly -Trp-Val-Thr-Asp-Gly-Phe45

Ser

25

-Ser-Leu-Lys-Asp-Tyr-Trp

50

Leu-Asp-Pro-GIu-Val-Arg-Pro-Thr-Ser-Ala-Val-Ala-Ala-C~ 70

(Gal,Gyl I 75

)-( NH2

NIN) 0,

I,2

FIG. 2. Amino acid sequence of human plasma very-low-density apolipoprotein apoC-III (apoLP-Ala) as described by Brewer et al. (70, 471). Carbohydrate moiety of apoC-III is attached to threonine residue 74 and contains 1 residue each of galactose (Gal) and galactosamine (GalNH,) and either 0, 1, or 2 residues of N-acetylneuraminic acid (NAN).

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these differences in sialic acid content. ApoC-III has been used extensively for the study of lipid-protein interactions (138, 231, 341, 342, 383, 510). Morrisett et al. (343) have reviewed these studies extensively. The physiologic functions of apoC-III are uncertain. Brown and Baginsky (78) have shown that apoC-III inhibits lipoprotein lipase at concentrations above 2% of the substrate (wt/ wt); the inhibition is not prevented by apoC-II. B. ApoB

Characterization of apoB has been hampered by technical problems in the solubilization and dissociation of lipid-free LDL (343). Although detergents (91, 189, 223, 259, 285, 309, 476), dissociating agents (189, 259, 437, 466, 482), and chemical modification (189, 259, 438) have been used to obtain soluble preparations of the lipid-free protein, there is no general agreement concerning the number of subunits or the molecular weight of apoB. Reported molecular weights of apoB range from 8000 to 275,000 (343), the most commonly reported values being in the range of 25,000-30,000. Both LDL and apoB have been studied by a number of physical methods (92, 186, 187, 188, 190, 192, 207, 208, 262, 303, 378, 490), the results of which have been summarized elsewhere (343). The optical studies suggest that LDL proteins contain relatively more p-structure than do the other lipoproteins. However, the spectral characteristics are sensitive to temperature and are affected by the carotenoids present in the lipoproteins (92). The quantity of this structure is decreased by delipidation of LDL, although the circular dichroism of apoLDL is qualitatively similar to that of the native lipoproteins. In general, the conformation of apoB is more labile to environmental perturbations and chemical modification in the delipidated state than in the intact particle. Although no sequence information is available about human apoB, the amino acid sequence of apovitellenin, a low-density apoprotein from the egg yolk of the emu (Dromains novae-hollandie), has been determined (105). Its homology to human apoB has not been established. C. ApoA

ApoA-I and apoA-II are the major protein constituents of HDL. ApoA-I is a single polypeptide chain of 245 amino acid residues (Fig. 3). The observed heterogeneity of this protein (12, 107, 313) has not been explained from the sequence information. Differences in amide content may account in part for the heterogeneity, although amino acid substitutions have not been excluded. Several investigators have studied the binding of apoA-I to phospholipids and detergents (20, 35, 140, 142, 239, 286, 312, 401, 433, 440, 498). Assmann and Brewer (20) have reported that apoA-I does not bind significant amounts of phospholipid in the absence of apoA-II, but others have observed binding (35, 239, 312). Variation in the phospholipid-binding properties of apoA-I may be related to the aggregation or solubility of the apoprotein (203, 401). The fact

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Asp - Glu - Pro - Pro - Gln - Ser - Pro - Trp - Asp - Arq - Val - Lys - Asp - Leu - Ala - Thr - Val - Tyr - Val - Asp IO 20

Val - LeU - LyS - Asp - SW - Gly - Arg - Asp - Tyr - Val - $er - Gln - Phe - Gin - Gly - Ser - Ala - Leu - G/y - ~~~ 30 40

Gln - Leu - Asn - Leu - Lys - Leu - Leu - Trp - Asp - Asp - Val - Thr - Ser - Thr - Phe - Ser - Lys - Leu - Arg - Gln 60 50

Glu - Leu - Gly - Pro - Val - Thr - Glu - Glu - Trp - Phe - Asn - Asp 70

Lys - Glu - Thr - Gly - Glu

Vat - Gln

Leu - Arq - Gln - Glu

Asp

Leu - Gln - Glu - Lys - Leu - Asn - Leu - Glu 80

Met - Ser - Lys - Asp - Leu - Glu - Glu - Val - Lys - Ala - Lys 90 100

Pro

Tyr

Leu - Asp

Lys - Val - Glu

Pro

Leu - Arq - Ala - Glu - Leu - Gln - Glu - Gly - Ala - Arg - Gln - Lys - Leu - His - Glu - Leu 130 140

Gln - Glu - Lys

leu -

Ser

- Pro - Leu -

Phe - Gln - Lys - lys - Trp - Gln - Glu - Met - Glu - Leu - Tyr - Arg - Gln 110 120

Gly

Glu - Glu - Met - Arg - Asp - Arg - Ala - Arg - Ala - His - Val - ASP 150 160

Ala - Leu - Arq - Thr - His - Leu - Ala - Pro - Tyr - Ser - Asp - Glu - Leu - Arg - Gln - Arg - Leu - Ala - Ala - Ar 170 1ail

Leu - Glu - Ala - Leu - Lys - Glu - Asn - Gly

Ala - Gly - Arg - Leu - Ala - Glu - Tyr - His - Ala - Lys - Ala - lhr 190 MO

Glu - His - Leu - Ser - Thr - Leu - Ser - Glu - Lys - Ala - Lys - Pro - Ala - Leu - Glu - Asp - Leu - Arq - Gin - GI 210 2&

Leu - Leu - Pro - Val - Leu - Glu - Ser - Phe - Lys - Val - Ser - Phe - Leu - Ser - Ala - Leu - Glu - Glu - Tyr - lhr 230 240

Lys - Leu - Asn - Thr - Gin 245 FIG.

as described

3. Amino acid sequence of human by Baker et al. (31-33, 100).

high-density

apolipoprotein

apoA-1

(apoL,P-Gin-I)

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April

LIPOPROTEIN

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STRUCTURE

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METABOLISM

that lysolecithin enhances phospholipid interaction with apoA-I (353, 517) suggests that disaggregation of the apoprotein may be a prerequisite for optimal binding. As determined by fluorescence spectroscopy, apoA-I is more resistant to denaturation when present in the intact HDL particle than the lipid-free protein (204). ApoA-I has been isolated from the cow (253), pig (98, 123, 240), rat (226, 273, 504), salmon (350), and from primates (64, 108). Purified apoA-I from each of these sources has an amino acid composition, molecular weight (approx. 27,000-28,000), and circular dichroic spectrum similar to that of the human apoprotein. The fact that apoA-I is similar over a wide range of species suggests that the apoprotein has a major structural and perhaps physiologic role. One such function is the activation of LCAT (128, 487). ApoA-I may also serve as an acceptor for cholesterol and cholesteryl ester during VLDL catabolism. Finally, it may have an important function in regulating the content of membrane lipids (249,495,497) and maintaining proper membrane fluidity (242). ApoA-II contains two identical polypeptide chains (69, 241, 314, 316, 434, 436) of 77 amino acid residues, which are linked by a disulfide bond at residue 6 (Fig. 4). As determined by circular dichroism, apoA-II is about 40% helical in its secondary structure (312). Reduction of the disulfide bond is associated with a 20% decrease in the content of a-helix (428); this change may be reversed by reoxidation. ApoA-II, reduced-alkylated apoA-II, or the COOHterminal cyanogen bromide fragment readily combine with phospholipid or with a phospholipid-neutral lipid mixture (243, 246, 312, 315).

r , Leu Gln Glu PbA

Ala

Lys Glu

Lys Ser

P:o Cys Val

Lys Glu

Phe Tyr Ser Lys Ala Gln

Glu Ser Lk’b Val Ser

Gln Tyr Phe Gln

10

Val Glu Ser Leu

Thr Val Thr i!?p Tyr Gly Lys Asp Leu

1q

Val Ser Gln Tyr Phe

'L,

n

Gln Thr Val Thr dsp

Tyr Gly Lys Asp ceu 1

50 /Thr Pro f

Leu Gln [ Glu

Lys I in the protein moiety in subjects with type II (292). In another recent development, possibly related to LDL catabolism, Starzl et al. (489) reported that a portal caval shunt resulted in a normalization of plasma lipids and a disappearance of xanthomata in a child who was a homozygote for hyperlipidemia. It should not be concluded that all patients with this disorder would necessarily respond in an identical way. The mechanism for cholesterol lowering by this procedure remains unknown. 9. HDL

catabolism

Very little is known about the fate of HDL in human circulation. In rats, the half-life of HDL in plasma is about 10.5 h (118,390, 411, 412) and the major site of catabolism is the liver (118, 390, 412). Bierman et al. (57) have also found that HDL particles may be catabolized by smooth muscle cells in culture. Roheim et al. (411) and Eisenberg et al. (118) have studied the rate of degradation of 1Z51-labeledHDL apoproteins in the rat. The radioactivity of apoA-II decays slower than that of apoC, possibly due to recirculation of the latter. Turnover studies in man are needed to determine whether these apoproteins are metabolized as a unit or individually. VI.

views

CONCLUSION

The plasma lipoproteins have not been discussed in PhysioLogical Refor nearly 20 years. Since that time, much has changed concerning our

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300 knowledge of this group of plasma proteins. Their heterogenous composition, complex structure, and intricate metabolism have led to a proliferation of studies and reports. We now know that the lipid and protein compositions of each lipoprotein class vary within the density range traditionally assigned to that class. The amino acid sequence of four lipoprotein proteins is known. Tentative models for HDL and LDL structures have been described. The amino acid sequences of apoB, apoC-II, arginine-rich protein, and thin-line protein remain to be established. Breakthroughs in methodology may be necessary for determination of the apoB sequence. Still undetermined is the precise mechanism(s) of lipid-protein interaction. The models proposed for LDL and HDL undoubtedly will be modified with the refinement of physical methods, such as NMR spectroscopy. Both VLDL and HDL are synthesized mainly by the liver; in man, LDL is largely a catabolic product resulting from VLDL degradation. The catabolism of LDL needs further study; some evidence points to nonhepatic sites of degradation. The relationship of LDL membrane receptors of fibroblasts and LDL catabolism needs clarification. Also, the relationship between the LDL receptor, cholesterol, LDL synthesis, and LDL catabolism in the intact organism must be elucidated. Virtually nothing is known concerning the mechanism and the control of synthesis and catabolism of the plasma lipoproteins. The relationships between altered lipoprotein structures and how they may relate to lipoprotein catabolism are still unknown. Answers to many of these problems in lipoprotein structure and metabolism will be slow in coming, but it can be anticipated that they may aid in our understanding of the various lipid-transport disorders. For example, can a defective apoA-I account for the deficiency of HDL in Tangier disease? Can a defective LDL membrane receptor explain the hypercholesterolemia in subjects with familial type II hyperlipoproteinemia? Is the absence of chylomicrons, VLDL, and LDL in abetalipoproteinemia accounted for by a defective apoB? Is the etiology of primary type I related to an abnormal triglyceride lipase? Finally, can this information be utilized to clarify the relationship between lipoproteins and the development of atherosclerosis? Over the next few years, we can look forward to a substantial increase in information about the plasma lipoproteins and it is anticipated that this will have applicability to general biological phenomena of life and health far beyond the macromolecular complexes being studied.

We thank our colleagues 0. David Taunton, James T. Sparrow, Baker, Henry J. Pownall, Henry F. Hoff, and, in particular, Louis criticism of this review. The tireless efforts of Ms. Debbie Mason manuscript are greatly appreciated. Work from the authors’ laboratory described in this review National Institutes of Health Grants HL-14194, HL-05435/34, and Jackson and Joel D. Morrisett are Established Investigators of The tion.

Josef Patsch, H. Nordean C. Smith for their helpful in the preparation of the was supported in part by HL-16512-01. Richard L. American Heart Associa-

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Lipoprotein structure and metabolism.

Physiological Reviews Published and Copyright by The American Physiological Society Lipoprotein RICHARD Baylor Vol. 56, No. 2, April Structure L...
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