Lipoprotein Metabolism

Lipoprotein Metabolism D. Roger Illingworth, MD, PhD • The pathways of cellular synthesis, assembly, and secretion of lipoproteins followed by their subsequent intravascular metabolism and cellular uptake provide an efficient system for the transport of exogenous and endogenous lipids. The present report reviews the pathways of normal lipoprotein metabolism and the roles played by specific apoproteins, transfer proteins, enzymes, and cellular receptors in facilitating the transport of lipids in plasma, as well as in the regulation of cellular cholesterol homeostasis. © 1993 by the National Kidney Foundation, Inc. INDEX WORDS: Cholesterol; plasma lipoproteins; chylomicrons; lipoprotein receptors; low-density lipoproteins.

T

HE ABILITY of lipids such as cholesterol, cholesteryl esters, and triglycerides, which are themselves insoluble in aqueous environments, to be transported in plasma is dependant on their incorporation into lipoprotein complexes that contain lipids in association with specific transport proteins termed "apoproteins" (apo). Historically, the separation of lipoproteins has been achieved by two principal techniques, electrophoresis and ultracentrifugation in salt solutions, and the classification oflipoproteins is most commonly expressed on the basis of their separation by ultracentrifugation. 1 Four major classes of lipoproteins are recognized; chylomicrons, very low-density lipoproteins (VLOL), low-density lipoproteins (LOL), and high-density lipoproteins (HOL). Each of these lipoproteins is heterogeneous in terms of size, lipid composition, and apoprotein content, and subfractions of the major lipoprotein classes can be isolated by electrophoresis, gradient ultracentrifugation, or affinity column chromatography. Low-density lipoproteins are often separated into two fractions, LOLl, also referred to as intermediate-density lipoprotein with a density of 1.006 to 1.019 g/ mL, and LOL2, which has a density of 1.019 to 1.063 g/mL. A fifth lipoprotein, lipoprotein (a) [Lp (a)], is present in plasma, and the majority From the Department 0/ Medicine, Division 0/ Endocrinology, Diabetes, and Clinical Nutrition, Oregon Health Sciences University, Portland, OR, Received November 2, 1992; accepted in revised/orm January II, 1993, Supported in part by National Institutes o/Health Research Grant No, HL28399, the General Clinical Research Center's Program RR334, and the Clinical Nutrition Research Unit (P30DK40566), Address reprint requests to D. Roger Illingworth, MD, PhD, Department ofMedicine, L465, Oregon Health Sciences University, Portland, OR 97201-3098. © 1993 by the National Kidney Foundation, Inc. 0272-6386/93/2201-0015$3.00/0 90

of this lipoprotein has a hydrated density between 1.06 and 1.08 g/mL. Lipoprotein (a) consists of an LOL particle to which an additional protein, termed "apoprotein (a)" is covalently bound. 2. 3 Typical values for the composition of the major plasma lipoproteins are shown in Table 1, whereas the apo content is illustrated in Table 2. LIPOPROTEIN COMPOSITION

Chylomicrons are the largest of the lipoprotein particles, with a diameter ranging from 800 A to 10,000 A. Following a lipid-rich meal, the fatty acid composition of chylomicron triglycerides resembles that of the consumed dietary fat. Human chylomicrons contain a form of apo B (B48), which is synthesized in the intestinal mucosal cells. Recent studies4 ,5 have indicated that B-48 represents a unique intestinal-derived form of apo B, which consists of the amino terminal 2152 amino acids of the normal hepatic apo B-lOO, which is 4536 amino acids in length. Apoprotein B-48 is produced from the apo B-I00 gene by a novel mechanism involving the editing of messenger RNA in the intestine, which results in the insertion of a stop codon (UAA) in place of the normal CAA codon, with the resultant termination of protein synthesis to produce a protein that is 2152 amino acids in length. The reason the intestine has the ability to synthesize this unique form of apo B is unclear; it could be speculated, however, that the smaller size of this protein allows for faster synthesis, which in turn may enable the intestine to rapidly adapt to variations in fat intake and maintain efficient absorption and synthesis of chylomicron particles. Very low-density lipoproteins constitute the major transport vehicle for endogenous triglycerides in plasma and are synthesized in the liver. Very low-density lipoprotein particles range in diameter from 300 A to 800 A, with larger par-

American Journal of Kidney Diseases, Vol 22, No 1 (July), 1993: pp 90-97

91

PHYSIOLOGY OF LIPOPROTEIN TRANSPORT Table 1. Composition of Human Plasma Lipoproteins

Protein Phospholipid Cholesterol free Cholesteryl ester Triglyceride Non-esterified fatty acid

Chylomicrons

VLDL

LDL

HDL

2 7 2 5 84

8 19 7 13 51

21 22 8 37 11

50 23 4 18 4

2

Note. Values are expressed as percentage of total dry weight of the lipoprotein.

ticles being present at times of increased hepatic triglyceride production. These particles contain apo B-lOO as their major apoprotein, but also contain the apo C polypeptides and apo E (Table 2). Low-density lipoproteins constitute the major carrier of cholesterol and cholesteryl esters in plasma (Table 1) and these lipoproteins contain apo B-100 as their major apoprotein (Table 2). High-density lipoproteins are the heaviest (density, 1.063 to 1.21 gjmL) and smallest (particle diameter, 90 A to 120 A) of the human lipoproteins and contain apoproteins A-I and AIl as their major protein moieties (Table 2). Lipoprotein (a) is an LDL-like particle that contains cholesterol, phospholipid, triglycerides, and apo B-lOO, with the latter linked via a single disulfide bond to a second large protein termed "apoprotein (a). ,,3 The structure of apo (a) is very similar to that of plasminogen, and apo (a) contains a number of pretzel-like structures termed "kringles." The molecular weight of apo (a) varies between 450,000 and 750,000; the relationship between molecular weight and plasma concentrations is an inverse one, with the highest plasma concentrations being observed in patients with the smallest molecular weight forms of apo (a). Increased plasma concentrations ofLp (a) are associated with an increased risk of atherosclerosis, but the precise physiologic function ofLp (a) remains unknown. 6 FUNCTION OF PLASMA APOPROTEINS

The apoprotein moieties of plasma lipoproteins serve unique functions in the biogenesis, transport, and metabolism of plasma lipoproteins. Eleven major apoproteins, A-I, A-II, AIV,

B-48, B-100, C-I, C-II, C-III, D, E, and apo (a), have been sequenced, and the genes responsible for their synthesis have been mapped in the human genome. 7,8 With the exception of apo (a), the amino acid sequences of the apoproteins contain domains that result in the formation of an amphipathic helix in which hydrophobic amino acids are arranged on one side and hydrophylic polar amino acids on the other. These properties contribute to the unique ability of the apoproteins to transport lipids in an aqueous environment. With the exception of apo B-48, apo B-lOO, and apo (a), all the apoproteins appear capable of disassociating from one lipoprotein and moving to another. This movement of apoproteins between lipoproteins not only serves to enhance metabolic processing of a given lipoprotein particle, but also prolongs the residence time of the apoproteins in plasma. With the exception of apo B-48 and probably apo A-IV, which are synthesized exclusively in the intestine, and apo A-II and B-lOO, which, in humans, are synthesized in the liver, biosynthesis ofapo A-I, C-I, CII, C-III, and E takes place in both the liver and intestine mucosal cells, as well as in certain other tissues, including muscle and macrophages. 9 Several of the apoproteins play distinct roles in the intravascular metabolism and cellular uptake of lipoproteins in addition to their role in the maintenance of lipoprotein stability (Table 3). Apoprotein C-II serves as a cofactor for lipoprotein lipase, the enzyme that hydrolyzes the triglycerides on plasma chylomicrons and VLDL, and a deficiency of apo C-II is associated with Table 2. Apoprotein Content of Human Plasma Lipoproteins Chylomicrons Major apoproteins Apo 8-48 Apo C-I Apo C-II Apo C-III Apo E Minor apoproteins Apo A-I ApoA-1i ApoA-IV ApoD

VLDL

Apo Apo Apo Apo Apo

LDL

Lp (a)

HDL

8-100 Apo 8-100 Apo 8-100 Apo A-I C-I Apo (a) Apo A-II C-II C-III E

Apo D

ApoC-1 ApoC-1I Apo C-III Apo E

Note. Apoproteins A-I, A-II, and A-IV each constitute 5% to 10% of the apoproteins in lymph chylomicrons but are minor components of the chylomicron particles present in plasma.

92

D. ROGER ILLINGWORTH

Table 3. Metabolic Functions of Plasma Apoproteins Apoprotein

A-I A-II A-IV 8-48 8-100 C-I C-II C-III D E

Transfer proteins

Molecular Weight

Metabolism Role

28,000 17,500 46,000 264,000 512,000

Activates LCAT Activates hepatic lipase; may inhibit LCAT Unknown, possibly involved in lipid transfer between lipoproteins Transport of lipids from the gut as chylomicrons Transport of lipids from the liver as VLDL and LDL; recognized by cellular LDL receptors Activates LCA T Activates lipoprotein lipase May inhibit activation of lipoprotein lipase by apo C-II May be involved in lipid transfer between lipoproteins Recognized by hepatic apo E receptors and cellular LDL receptors; recognition facilitates hepatic uptake of chylomicron and VLDL remnants Facilitate the transfer of triglycerides, phospholipids, and cholesteryl esters between lipoproteins

7,000 9,000 9,000 22,000 34,000

Variable

Abbreviation: LCAT, lecithin cholesteryl-acyltransferase.

severe hypertriglyceridemia. 10 • 11 Apoprotein A-I, the major apoprotein of HDL, is a co-factor for lecithin cholesterol-acyltransferase (LCA T), the plasma enzyme that catalyzes the conversion of cholesterol to cholesteryl esters using the fatty acid from the 2 position of phosphatidyl choline. 12 Apoproteins E and B-I00 serve unique roles in facilitating the receptor-mediated catabolism of lipoproteins. Apoprotein E is the ligand that facilitates the receptor-mediated uptake of chylomicron and VLDL remnant particles by the liver. 13 The hepatic uptake of chylomicron remnants does not require the interaction of apo B48 with hepatic receptors, but the removal of LDL particles from plasma is facilitated by binding domains present in the C-terminal portion of apo B-1 00, which are recognized by specific highaffinity LDL receptors. 5 Monoclonal antibodies directed against epitopes on apo B-I00 located between amino acids 2980 and 3780 completely block the specific binding ofLDL particles to the LDL receptor, and indicate that this region of apo B-I00 contains the receptor-binding domain. 5 These studies are also consistent with the observation that patients with familial defective apo B-lOO, in which the amino acid glutamine is substituted for the normal arginine at position 3500, exhibit increased plasma concentrations of LDL and that the LDL particles isolated from the plasma of these patients show impaired binding to LDL receptors on cultured human cells

and, in vivo, show delayed clearance from plasma. 14 ENZYMES AND TRANSFER PROTEINS INVOLVED IN LIPOPROTEIN METABOLISM

Three enzymes, lipoprotein lipase, hepatic lipase, and LCA T are of physiologic importance in the metabolism of plasma lipoproteins. In addition, a specific transfer protein, cholesteryl ester transfer protein (CETP), facilitates the interchange of cholesteryl esters between HDL and triglyceride-rich lipoproteins and the reciprocal transfer of triglycerides in the reverse direction. Lipoprotein lipase is a hydrolytic enzyme that is present primarily on endothelial cells in the capillary beds of a number of tissues, including muscle, adipose tissue, and breast tissue. 15 The enzyme is normally present in plasma in very low concentrations, but may be released by the injection of heparin. Physiologically, this enzyme acts to hydrolyze triglycerides present in chylomicron and VLDL particles, and optimal activity of this enzyme necessitates the presence of apo C-II, which acts as a specific activator. Mutations in the gene for lipoprotein lipase that result in an absence of functional enzyme are associated with severe hypertriglyceridemia and the accumulation of chylomicron and, to a lesser extent, VLDL particles in plasma. 16 The activity of lipoprotein lipase in adipose tissue is increased in response to the administration of insulin, and

PHYSIOLOGY OF LIPOPROTEIN TRANSPORT

93

is reduced by fasting and by the presence of uremia. ls Hepatic lipase is a distinct hydrolytic enzyme present on hepatocyte cell membranes that can be released into plasma by the intravenous injection of heparin. 17 Deficiency of hepatic lipase has been associated with the accumulation of small triglyceride-rich VLDL particles in plasma, as well as an increase in the concentrations of the lighter HDL subfraction HDL2.IS Hepatic lipase does not appear to be involved in the initial delipidation of chylomicron and VLDL particles, and its role appears to be primarily to facilitate the further catabolism of chylomicron and VLDL remnants at the hepatocyte cell membrane. Lecithin cholesterol-acyltransferase is an enzyme present in plasma that catalyzes the transfer of a fatty acid from the 2 position of phosphatidyl choline to cholesterol, with the resultant formation of a cholesteryl ester molecule and lysophosphatidyl choline. The enzyme acts on lipids that are constituents of HDL and results in the formation of most of the esterified cholesterol present in plasma. Lecithin cholesteryl-acyltransferase is activated by apo A-I and apo C-1. Deficiency of LCA T is associated with increased plasma concentrations of non-esterified cholesterol, which results in increased tissue concentrations of free cholesterol and the premature development of atherosclerosis and progressive renal insufficiency" 9 Cholesterol ester transfer protein is a plasma protein that facilitates the transfer of cholesteryl esters from HDL particles to VLDL, with a reciprocal transfer of triglycerides from VLDL to HDL. 20 Cholesterol ester transfer protein activity has been shown to be increased in hypertriglyceridemia and in patients with diabetes, but is decreased in response to alcohol consumption. 2o A genetic deficiency of CETP has been described in Japan and has been associated with marked increases in the plasma concentrations of HDL cholesterol; this clinical entity lends support to the view that CETP is important in the normal transfer of cholesteryl esters between plasma lipoproteins. 21

rate-limiting in the absorption of dietary lipids, and the synthesis and secretion of chylomicron particles is dependant on the intracellular assembly of the constitutive lipids (triglycerides, cholesteryl esters, retinyl palmitate, and phospholipids) and concurrent synthesis of apo A-I, AIV, B-48, and, possibly, some C and E apoproteins. Following release from the intestinal mucosal cells into the lymph, nascent chylomicrons enter the systemic circulation via the thoracic duct, and are normally rapidly metabolized with a plasma half-life of 5 to 15 minutes. Transfer of apo A-I and apo A-II to HDL and reciprocal transfers of C and E apoproteins from HDL serve to enhance the hydrolysis of chylomicron-triglycerides by the enzyme lipoprotein lipase, and provide a source of chylomicron surface components that act as precursors of nascent HDL particles (Fig I). Lipolysis of chylomicron-triglycerides by the enzyme lipoprotein lipase occurs predominantly in the capillary beds of muscle and adipose tissue, and results in progress delipidation of the chylomicron particle. Very low-density lipoprotein particles compete with chylomicrons for lipopro-

CHYLOMICRON METABOLISM

Fig 1. Metabolic transformation of chylomicron particles and the interconversions that occur between chylomicrons and HDL. HDL2, HDL with a density between 1.063 and 1.125 g/mL; HDL3, HDL with a density between 1.125 and 1.21 g/mL; FFA, free fatty acids; LPL, lipoprotein lipase.

Chylomicrons are synthesized in the small intestine in response to the absorption of dietary fat. Chylomicron synthesis does not appear to be

Intestine

94

D. ROGER ILLINGWORTH

tein lipase-mediated catabolism, but chylomicrons appear to be the preferred substrate. Progressive hydrolysis of chylomicron-triglyceride leads to the formation of a smaller chylomicron particle, termed a "chylomicron remnant," which contains almost all the cholesterol originally contained in the nascent particle and several molecules of apo E but which has lost most of the C apoproteins. The uptake of chylomicron remnants is dependant on a specific hepatic receptor that has been termed the "LDL receptorrelated protein," and this receptor recognizes the apo E moieties contained on the chylomicron remnant particles and facilitates their uptake from plasma.2 2 Receptor-mediated uptake of chylomicron remnant particles by the liver leads to an increased hepatic cholesterol content and is associated with a concurrent decrease in hepatic cholesterol biosynthesis. Genetic or acquired defects in lipoprotein lipase may lead to the abnormal accumulation of chylomicron particles in plasma, whereas abnormalities in chylomicron remnant catabolism lead to the accumulation of potentially atherogenic chylomicron remnant particles. The importance of apo E in facilitating the hepatic clearance of remnant lipoproteins is well-illustrated by the metabolic consequences, which result from substitution of the amino acid cysteine for the normal arginine at position 158 in the apo E molecule; this change leads to impaired receptor binding of apo E and is the most common abnormality in patients with type III hyperlipidemia, in whom VLDL and chylomicron-remnant particles accumulate in plasma. 23 VERY LOW-DENSITY LIPOPROTEIN METABOLISM

The liver is the major site of synthesis of VLDL, for which apo B-IOO is a constitutive apoprotein. Very low-density lipoprotein particles serve to transport endogenous triglycerides from the liver to peripheral tissues, and intravascular hydrolysis ofVLDL triglycerides depends on the activity of lipoprotein lipase (Fig 2). The metabolism ofVLDL and chylomicron particles show many similarities, but one important difference is that the remnant particles, which result from VLDL lipolysis, can be either taken up by the liver via apo E-mediated catabolism or subsequently converted to LDL. Metabolism ofVLDL to LDL is the major source of the latter lipopro-

tein in human plasma. Many factors, including nutrient intake, plasma concentration of freefatty acids, and levels of insulin, glucagon, and epinephrine in plasma, appear to modulate the secretion of hepatic VLDL, which in turn influences VLDL concentrations in plasma. The catabolism ofVLDL remnant particles by the liver is facilitated by their binding to both high-affinity LDL receptors as well as to the LDL receptorlike protein. 13,22 In normotriglyceridemic human subjects, virtually all the apo B that enters plasma as a constituent ofVLDL is preserved as the particle is metabolized to intermediate-density lipoproteins and to LDL. In contrast, in patients with severe hypertriglyceridemia, most of the VLDL particles are removed prior to conversion to LDL, resulting in low plasma concentrations ofLDL in this patient population. This precursorproduct relationship between VLDL and LDL is seen clinically in patients with moderate hypertriglyceridemia who are treated with either diet or drugs and in whom initial decreases in VLDL are not uncommonly accompanied by reciprocal increases in the plasma concentrations of LDL. Very low-density lipoprotein particles are metabolized slower than chylomicrons and, under normal circumstances, the half-life ofVLDL apo B is 6 to 12 hours. Moderate hypertriglyceridemia with plasma triglycerides between 300 and 800 mg/dL usually reflects the accumulation of endogenous VLDL particles in plasma; such an accumulation may result from enhanced rates of VLDL synthesis, genetic or acquired defects in triglyceride hydrolysis, or combinations of both. An accumulation of VLDL remnant particles occurs in the plasma of patients with type III hyperlipidemia or in patients with hepatic lipase deficiency.18.23 LOW-DENSITY LIPOPROTEIN METABOLISM

In humans, LDL is the major cholesterol-carrying particle present in plasma and, metabolically, LDL may be regarded as the end product of VLDL metabolism (Fig 2). The catabolism of LDL occurs in both peripheral tissues and the liver, but the liver is responsible for the catabolism of70% of LDL in normal human subjects. Lowdensity lipoprotein catabolism is facilitated by both receptor-mediated and non-receptor-mediated pathways, but in normal human subjects, the receptor-mediated pathway predominates and

95

PHYSIOLOGY OF LIPOPROTEIN TRANSPORT CD 9-100

(S2

Liver Acetate

Fig 2. Metabolic interconversions of VLDL and LDL in plasma and the intracellular effects of receptor-mediated uptake of LDL. FFA, free fatty acids; HDL2, HDL with a density between 1.063 and 1.125 g/mL; LPL, lipoprotein lipase; HMG CoA, hydroxymethyl glutacyl coenzyme A; PL, phospholipid; TG, triglyceride; HTGL, hepatic triglyceride lipase.

t Cholesterol

I

)

~E 8-100

VlDL CD

E

~ em

FFA

lPL

......

~

_ -_ _

Muscle Adipose Tissue

~~rAPOEMedl8ledUPtake 8-100 --- TG / / J E@ E

. . ~B-...::.. PL

Uptake

is responsible for the clearance of up to 75% of the plasma LDL pool. The studies of Russell et al 24 and Hobbs et al 25 have led to a precise understanding of the biochemistry and regulation of specific high-affinity LDL receptors, which appear to be present on virtually all cells, including hepatocytes, mononuclear leukocytes, and cells in steroid hormone-producing tissues. The uptake ofLDL by receptor-mediated endocytosis results in the suppression of endogenous cholesterol biosynthesis, an enhanced rate of intracellular cholesteryl esterification, and a reduction in the number of high-affinity LDL receptors expressed on the cell surface (Fig 2). The importance of the LDL receptor in the regulation of LDL concentrations in plasma is exemplified by the severe hypercholesterolemia seen in patients with both heterozygous and homozygous familial hypercholesterolemia, in whom LDL receptors are reduced by 50% (heterozygotes) or are totally absent (receptor-negative homozygotes).26 Hypercholesterolemia, with increased plasma concentrations of LDL cholesterol, may result from a number of genetic and acquired disorders that lead to either an enhanced rate of VLDL and LDL apo B synthesis, from genetic or acquired defects in LDL catabolism (resulting from impaired expression of high-affinity LDL receptors), from defects in the receptor-binding domain of LDL (which also lead to an impairment in LDL catabolism), or from combined defects resulting in enhanced synthesis and impaired catabolism. The hypercholesterolemia seen in patients with the nephrotic syndrome is an example of an acquired disorder in which high levels of LDL cholesterol appear to result from a combination

HTGL

VLDL

~- ______ ..

Remnant

@

n_. "" ........ ""', ------___

CO,

-..

~!"

-;7 ______

Receptor

'-....

LOl

{~:~:c~ao~ .l

catabolism,

cholesterol

t

cholesterol

~!~PIOI S

1

release of

esterification

of increased synthesis and impaired catabolism ofLDL. 27 HIGH-DENSITY LIPOPROTEIN METABOLISM

High-density lipoproteins are derived from both direct synthesis in the liver and from the surface components of chylomicron and VLDL particles, which are generated during intravascular lipolysis (Fig 1). This dual etiology for HDL explains the inverse correlation between plasma triglycerides and HDL as well as the known presence of HDL particles in the plasma of patients with abetalipoproteinemia, a disorder in which chylomicrons, VLDL, and LDL are absent from plasma. Newly synthesized HDL particles appear as disk-shaped structures that contain predominantly protein, free cholesterol, and phospholipid, but which, when exposed to the action of LeAT, are transformed into spherical particles rich in cholesteryl esters. 28 The apoprotein content of individual HDL particles varies and it is apparent that some HDL particles contain both apo A-I and apo A-II, whereas others may only contain apo A-I. The half-life of HDL, as assessed by that of its constituent apoproteins, apo A-I and apo A-II, is from 4 to 6 days and is influenced by both diet and a number of pharmaceutical agents. Thus, diets high in carbohydrate, which raise VLDL, cause a reduction in HDL concentrations and an enhanced rate of HDL turnover, whereas nicotinic acid, which depresses VLDL synthesis, raises the concentrations of HDL and prolongs the half-life of apo A-I in plasma. Epidemiologic studies have shown an inverse correlation between the plasma concentrations of HDL cholesterol and the risk of coronary artery

96

D. ROGER ILLINGWORTH

disease 29 and have led to the proposal 30 that one major function of HDL is to transport cholesterol from peripheral tissues back to the liver. Physiologic evidence to support this is not strong. Several factors have been shown to increase the concentrations ofHDL in plasma predominantly by affecting concentrations of the lighter HDL2 subfraction. Factors that have been shown to increase HDL concentrations include a moderate consumption of alcohol, sustained regular exercise, and correction of hypertriglyceridemia. 31 •32 As previously discussed, a deficiency of CETP also has been associated with increased plasma concentrations ofHDL cholestero1. 21 In addition to environmental factors, a number of genetic disorders have been described in which the metabolism and concentrations ofHDL particles are profoundly altered; these disorders illustrate the important roles played by apo A-I and A-II in the synthesis and metabolism of HDL particles in humans. 28 With the exception of familial hyperalphalipoproteinemia and CETP deficiency, which are both associated with increased plasma concentrations ofHDL cholesterol, other genetic disorders that influence lipoprotein metabolism result in reduced plasma concentrations ofHDL cholesterol and its constituent apoproteins. Some, but not all of these disorders are associated with an increased risk of coronary artery disease.

SUMMARY The physiologic basis of lipid transport in humans is now well-delineated, and it is apparent that a number of factors, both genetic and acquired, can influence this transport system and result in abnormal concentrations of lipoproteins in plasma. Increased plasma concentrations of LDL, Lp (a), and cholesterol-rich VLDL and chylomicron remnants all appear to be highly atherogenic, whereas, on the basis of epidemiologic studies, increased concentrations of HDL cholesterol appear to afford protection from the premature development of atherosclerosis. Modifications in lipoproteins, particularly oxidation or glycosylation of LDL, may also affect the metabolism of these lipoproteins and result in enhanced rates of uptake by "scavenger receptors" present on tissue macrophages, with the resultant formation of foam cells. 33 . 34 It is believed that oxidation of LDL particles occurs in atherosclerotic plaques, but local oxidation of LDL may

occur under conditions of endothelial cell injury and potentially under other circumstances in which plasma concentrations of natural antioxidants are reduced. A thorough understanding of the normal and abnormal pathways of lipoprotein metabolism should enable future studies to better define the role, if any, of modified lipoproteins and antioxidant therapy in the pathogenesis of arterial injury and atherosclerosis.

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PHYSIOLOGY OF LIPOPROTEIN TRANSPORT

18. Breckenridge WC, Little JA, Alaupovic P, Wang CS, Kaksis A, Lindgren F, Gardiner G: Lipoprotein abnormalities associated with a familial deficiency of hepatic lipase. Atherosclerosis 45: 161-170, 1982 19. Norum KR, Gjone E, Glomset JA: Familial lecithin cholesterol acyltransferase deficiency including fish eye disease, in Scriver CR, Beaudet AL, Sly WS, Valle D, (eds.) The Metabolic Basis of Inherited Disease (ed 6). New York, NY, McGraw-Hill, 1989, pp 1181-1194 20. Editorial: Cholesterol-ester transfer protein. Lancet 338: 666-668, 1991 21. Inazu A, Brown ML, Hesler CB, Agellon LB, Koizumi J , Takata K, Maruhama Y, Mabuchi H, Tall AR: Increased high density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. N Engl J Med 323: 1234-1238, 1990 22. Brown MS, Herz J, Kowal RC, Goldstein JL: The LDL receptor-related protein (LRP): Double agent or decoy? Curr Opin Lipidol 2:65-72, 1991 23. Mahley RW, Rao SC, Jr: Type !II hyperlipidemia (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 (ed 6). New York, NY, McGraw-Hili, 1989, pp 11951213 24. Russell DW, Esser V, Hobbs HH: Molecular basis of familial hypercholesterolemia. Arteriosclerosis 9:1-8-1-13, 1989 (suppl) 25. Hobbs HH, Russell DW, Brown MS, Goldstein JL: The LDL receptor locus in familial hypercholesterolemia:

97 Mutational analysis ofa membrane protein. Annu Rev Genet 24:133-148, 1990 26. Bilheimer DW, Stone NJ, Grundy SM: Metabolic studies in familial hypercholesterolemia: Evidence for a gene/ dosage effect in vivo. J Clin Invest 64:524-532, 1979 27. Warwick GL, Caslake NJ, Boulton-Jones JM, Dagen M, Packard CJ, Shephard J: Low density lipoprotein metabolism in the nephrotic syndrome. Metabolism 39:187-192, 1990 28. Brewer HB, Jr, Raider DJ: HDL: Structure, function and metabolism. Prog Lipid Res 30: 139-144, 1991 29. Abbott RD, Wilson BWF, Kanel WB, Castelli WP: High density lipoprotein cholesterol, total cholesterol screening and myocardial infarction. Arteriosclerosis 8:207-211, 1988 30. Glomset JA, Norum KR: The metabolic role oflecithin cholesterol acyltransferase: Perspectives from pathology. Adv Lipid Res 11:1-18,1973 31. Krauss RM: Regulation of high density lipoprotein levels. Med Clin North Am 66:403-417, 1982 32. Williams PJ, Krauss RM, Wood PD, Albers JJ, Dreon D, Ellsworth N: Association of diet and alcohol intake with high density lipoprotein subclasses. Metabolism 34:524-529, 1985 33. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL: Beyond cholesterol: Modifications of low density lipoprotein that increases its atherogenecity. N Engl J Med 320:915-924, 1989 34. Gaziano JM, Hennekens CH: Vitamin antioxidants and cardiovascular disease. CUff Opin Lipidol 3:291-294, 1992