Lipid transfer proteins, hypertriglyceridemia, and reduced high-density lipoprotein cholesterol

EDlTOR1AlS

Daniel Sparks, PhD, Jiri J. Frohlich, MD, and P. Haydn Pritchard, PhD. Vancouver, British Columbia, Canada

For over 15 years it has been accepted that a low plasma high-density lipoprotein (HDL)-cholesterol represents a significant independent risk factor for coronary artery disease.l More recently, other studies2 have shown that elevated HDL-triglyceride levels may also be related to the incidence of heart disease. While these observations suggest that the development of coronary artery disease may be asao- ciated with changes in HDL mass and composition, there haa been no clear understanding of the mechanism by which low HDL-cholesterol or abnormal HDL composition may be involved in the process of atherogenesis. Studies have shown, however, that HDL lipid composition may be markedly affected by a neutral lipid transfer protein called cholesteryl ester transfer protein (CETP or LTP-I).3-5 Some in- vestigators5t6 have suggested that elevated CETP activity may promote atherogenesis by stimulating increased transfer of cholesteryl esters to low-density lipoproteins (LDL) in patients with low HDL-cholesterol. Our investigations support this hypoth- esis7* *; however, these studies suggest that the specific activity of CETP may less important in regulating the net movement of cholesteryl ester than other factors that govern the relative rates of transfer of this lipid between different lipoprotein classes. We propose that the net movement of cholesteryl ester into or out of HDL is centrally dependent on the composition of this lipoprotein.

Choiesteryl ester transport and clearance. CETP was originally identified as a plasma activity that promoted the accumulation of newly synthesized cho- leeteryl esters in apo B-containing lipoproteins after in vitro incubation of plasma.g This suggested that

From the University Hospital Lipid Research Group, Department of Pathology, University of British Columbia.

Received for publication Dec. 10, 1990; accepted Jan. 21, 1991.

Reprint requests: Daniel Sparks, PhD, Department of Physiology and Bio- chemistry, The Medical College of Pennsylvania, 3300 Henry Ave., Phila- delphia, PA 19129.

4/l/29750

CETP promoted the movement of c 1 ester into rapidly cleared lipoproteins, and led to the development of the concept of reverse transport-a pathway through whichch be removed from the plasmal* It also prompted a flurry of investigations that focused on t&e c&pa&y of CETP to promote the transfe of elm into LDL and the factors that Cholesteryl ester transfer to LD beneficial, as protein turnover studiee s LDL turnover was much faster than fore lipid transfer to this fraction may promote

lesterol levels 0 olemia, it could not explain elevations in LDL- cholesterol in disorders where no apparent.l’? l2 Increased LDE- could, however, also cholesteryl ester into hepatic LDL clearance. movement, CETP may indeed activity and therefore a deficie The concept seems to be s reports13> l4 of a CE sents with markedly and apparently a low r Accordingly, some that low HDL-chol increased CETP activity, w transfer of cholesteryl eater from HDL to LDL. This hypothesis, however, implies that CETP can only promote a net movement of choles~ryl ester into LDL, and does not explain the recent reports that clearly indicate that a net movement of choloeteryl ester into HDL can also oc~ur.~~~ l6

Cholesteryt ester treneport in @asma. The most pop-

601

602 Sparks, Frohlich, and Pritchard August 1991

American Heart Journal

A. Normolipidemia (fasting)

Net mass transfer r=+

B. Hyperlipidemia

Net mass transfer +J

Fig. 1. Variations in the rates of lipid transfer result in mass transfer. In normal fasting plasma, the rate of influx of cholesteryl ester into HDL is greater than the efflux, resulting in a net mass movement into HDL. In lipemia, however, altered HDL composition impairs the influx of cholesteryl ester into HDL but has little effect on the efflux, which then results in a net movement of cholesteryl ester into the LDL.

ular misconception regarding the movement of cholesteryl ester in the plasma is that a net movement of this lipid only occurs from HDL to LDL. On the con- trary, several laboratories have now shown that a net movement of cholesteryl ester from apo B-containing lipoproteins into HDL occurs in incubations of normolipidemic fasting plasma.15-17 In vitro incubations of plasma from normal fasting subjects have demonstrated a net increase in HDL cholesteryl ester content.15p l6 In these studies, this increase was shown to be significantly higher than the amount of cholesteryl ester that was produced by lecithin: cholesterol acyltransferase (LCAT), and therefore both studies concluded that there was substantial net transfer of cholesteryl ester from LDL into HDL. In contrast, incubations of normal postprandial plasma have demonstrated a reduction in HDL-cholesterol resulting from a net transfer of cholesteryl ester from HDL to LDL.16-ls A similar net transport of cholesteryl ester into LDL has been demonstrated in incubations of plasma from hyperlipidemic subjects, both in baboonsI and in humans.17p I9 These studies suggest that in fasting normolipidemia, there is a net movement of cholesteryl ester into HDL, but in lipemia, whether it be postprandial or dyslipidemic, there is a net movement of cholesteryl ester out of HDL (Fig. 1).

Cholesteryl ester influx and efflux from HDL. CETP can facilitate the transfer and exchange of neutral lipids between all classes of lipoproteins.20 Investiga-

tions have still not resolved the mechanism by which CETP transfers neutral lipid; however, two different models have been proposed. One model leads to the conclusion that CETP acts as a carrier protein, where CETP carries the lipid between different lipoproteins, much as other transfer proteins operate.21 Much of the experimental and kinetic evidence,3* 22 however, supports a different model in which neutral lipid transfer occurs through the formation of a ter- nary complex of CETP, donor, and acceptor lipoproteins. These studies have shown that CETP can promote an exchange of lipids, whereby cholesteryl ester is exchanged for a molecule of cholesteryl ester between HDL and other cholesteryl ester-rich lipoproteins (LDL), while a reciprocal exchange of cholesteryl ester for triglyceride occurs between HDL and triglyceride-rich lipoproteins37 5 This heteroexchange of neutral lipid has been the most accepted mechanism underlying the net movement of cholesteryl ester into triglyceride-rich lipoproteins.5 Studies have shown, however, that a net movement of cholesteryl ester can also occur between cholesteryl ester-rich substrates, such as between LDL and HDL.15p l6 Since this could not be facilitated by a heteroexchange, these studies suggest that net cholesteryl ester transport between particles with a pre- dominantly cholesteryl ester core must be independent of a reciprocal lipid exchange. This postulate is supported by the recent observations of Barter et al.,23 which suggest that both fatty acid-poor albumin and sodium oleate can disrupt the CETP-mediated equilibrium between HDL and LDL, and either inhibit (albumin) or promote the unidirectional transfer of cholesteryl ester from HDL to LDL. While the mechanisms involved and the physiologic significance of these observations are unclear, they do indicate that a net lipid movement can occur between LDL and HDL, without a reciprocal exchange component.

If net lipid transfer occurs without a heteroexchange component, changes in the rates of cholesteryl ester transfer into and out of the HDL pool may be central in a net lipid movement. In fact, several studies3-81 23V27 have clearly shown that HDL may act as both a donor and recipient of cholesteryl ester. Some investigations 7, & 25-27 have further shown that specific HDL subfractions may be preferred CETP substrates and excellent acceptors of cholesteryl ester. If there is cholesteryl ester influx as well as efflux from HDL, the net movement of cholesteryl ester out of HDL must reflect differences in the relative rates of influx and efflux. Changes in the relative rates of influx and efflux must directly affect the net movement of cholesteryl ester. If this is the case in vivo, the

voIumo 122 Number 2 HDL composition and cholestervl ester transport 603

factors that govern these rates of influx and efflux may indeed be central to the development of low HDL-cholesterol levels.

Direct estimations of choleateryl ester mass transfers in normal and hyperlipidemic subjects have demonstrated a net movement of cholesteryl ester into HDL in fasting normolipidemic plasma and out of HDL in both postprandial and dyslipidemic plasma.16, la, lg The se studies showed that variations in mass transfer were closely related to changes in efflux with respect to influx. In fasting plasma, cholesteryl ester mass movement was shown to result from a high rate of cholesteryl ester influx into HDL, which exceeds the rates of cholesteryl ester production by LCAT and the efflux of cholesteryl ester from the HDL pool (Fig. 1, A). In contrast, in normolipidemic poatprandial plasma (Fig. 1, B), net transport of cholesteryl ester out of HDL was shown be a result of a marked reduction in the rate of transfer from apo B-containing lipoproteins into HDL and an increase in the efflux from HDL.16 This was also observed in both fasting and postprandial hyperlipidemic subjects.16 As in the normolipidemic postprandial plasma, a net mass transfer of cholesteryl ester out of the hyperlipidemic HDL was associated with a marked drop in the rate of transfer of cholesteryl ester into HDL (Fig. 1, B).

A disparity in the rate of influx with respect to efflux must result in a net movement of cholesteryl ester. In fact, this has been demonstrated in one study,25 where Morton showed that increased HDL free cholesterol promoted a net movement of cholesteryl ester out of HDL, which was concomitant with a reduction in the rate of influx of cholesteryl ester into HDL. In Morton’s study, it was shown that increased free cholesterol content markedly affects the ability of HDL to receive cholesteryl ester but has no effect on the ability of apo B-containing lipoproteins to receive this lipid. In addition, in a very recent report, Morton and Greene26 have further shown that the plasma protein that they and others27 have shown to inhibit CETP can selectively inhibit transfer reactions between specific lipoprotein classes and in so doing promote the net transfer of HDL cholesteryl ester mass into LDL.26 These studies show that the influx and efflux of cholesteryl ester from HDL may be independently regulated. They also indicate that a net movement of cholesteryl ester from the HDL pool will result if the influx falls relative to cholesteryl ester efflux. We have shown that increases in HDL triglyceride or free cholesterol content both reduce the rate of influx of cholesteryl ester into HDL.7r 8 We propose, therefore, that the abnormal HDL composition associated with hyperlipidemia promotes a net

mass movement of cholesteryl ester out of HDL (Fig. 1, B).

HDL compositlon and CETP. Several studies2. ‘, ‘& ” have shown that HDL lipid composition may be markedly altered in patients with disorders of lipid metabolism. The most notable change observed in hyperlipidemic patients has been a striking increase in HDL triglyceride levels with a concomitant fall in HDL-cholesteryl ester. 2, 7, 28 The causes of elevated HDL-triglyceride as a result of postprandial or dyslipidemic hypertriglyceridemia have been extensively reviewed and have been shown to be closely linked to the actions of both hepatic and lipoprotein lipase.30331 One study2 has further shown that elevated HDL-triglyceride may be an independent risk factor for coronary artery disease. As such, it seems likely that since 75% of HDL cholesterol is cholesteryl ester, perhaps the widely accepted risk factor for heart disease, low HDL-cholesterol, is directly related to elevated HDL-triglyceride.

Investigations in this laboratory79 R have shown that changes in HDL composition are associated with reduced ability of the HDL pool to accept cholesteryl esters. In a comparative study of normal and dyslipidemic subjects,7 we showed that cholesteryl ester transfer in fasted normolipidemic subjects was equally distributed, with 50% going to HDL and the rest going to apo B-containing lipoproteins (Fig. 2). Cholesteryl ester transfer in patients’ plasma, however, was notably shifted to the LDL, with significantly reduced transfer to the HDL pool and, in some cases, significantly increased transfer of cholesteryl ester to apo B-containing particles (Fig. 2). Reduced transfer of cholesteryl ester to HDL was shown to be directly related to an altered HDL composition and, interestingly, was demonstrated in patients with normal HDL mass as well as in those with reduced HDL levels.7

The capacity of CETP to promote the transfer to and possible accumulation of cholesteryl esters in LDL has resulted in some suggestions that CETP might play an important role in atherogenesis.5$ 32 Interestingly, several species that have been shown to have low plasma CETP activities, such as the dog, rat, pig, cow, and sheep,33 have also been shown to have low plasma LDL esterified cholesterol levels and also tend to be resistant to the development of atherosclerosis.32 This concept is supported by studies in hypercholesterolemic rabbits that identified increased CETP-mediated cholesteryl ester transfer from HDL to apo B-containing particles and subse- quent accumulation of these cholesteryl esters in cultured macrophages.6 In the same report, Tall et al6 also demonstrated accelerated CETP-mediated

604 Sparks, Frohlich, and Pritchard August 1991

American Heart Journal

CET ACTIVITY (%/mL/h)

NORMAL Hyper C6Tg Hyper C Hypoalpha (27) (19) (7) (6) T

m CET to LDLllVLDL @?!d CET to HDL

Fig. 2. Cholesteryl ester transfer from solid-phase-bound HDL to plasma lipoproteins. Eight hundred microliters of plasma was incubated with 200 pg solid-phase-bound HDL protein for 1 hour at 37’ C. The rate of cholesteryl ester transferred from immobilized HDL to plasma lipoproteins was determined as previously described.25 NORMAL,, Normolipidemia; Hyper C&Tg, familial combined hyperlipidemia; Hyper C, familial hypercholesterolemia; Hypoalpha, hypoalphalipoproteinemia; Dysbeta, dysbetalipoproteine- mia. Results are expressed as means f S.D. Significance of difference from controls: ***p < 0.001. (Adapt- ed with permission from Sparks DL, et al. Atherosclerosis 1989;77:183-91.)

12-

r = -0.988

r = -0.965 t-

3-

0 4 6 12 16 4 6 8 10 12

RELATIVE TRIGLYCERIDE RELATIVE FREE CHOLESTEROL CONTENT (X by weight) CONTENT (X by weight)

Tmax = maximum velocity of CE transfer

Fig. 3. Effect of rHDL lipid composition on the velocity of lipid transfer into rHDL. The maximum velocities of cholesteryl ester transfer (T,,,) into reconstituted HDL (rHDL) were estimated as previously described36 and are plotted against rHDL triglyceride (A) and free cholesterol (B) contents. Correlation coefficients (r) were determined by regression analysis. (Adapted with permission from Sparks DL, and Pritchard PH. J Lipid Res 1989;30: 1491-8.)

cholesteryl ester transfer from HDL to LDL and very low-density lipoprotein (VLDL) in dysbetalipopro- teinemic patients. Investigations in this laboratory7 have also observed an increased rate of cholesteryl ester transferred to the LDL in dysbetalipoproteine- mic patients and also in individuals with hypoalphalipoproteinemia (Fig. 2). In this study, however,

apo A-II

1

-60 0 60 100 160 200 + CONTROL CE TRANSFER ACTIVITY

Fig. 4. Effect of apoprotein content on lipid transfer into HDL. The transfer of [3H]cholesteryl ester from labeled LDL to HDL and purified apoproteins is shown. Mixtures containing partially purified CETP (1.3 tip), LDL (30 rg total cholesterol), BSA (1 mg), HDL (30 rg total cholesterol), and purified apoproteins (25 pg protein) were incubated at 37O C for 1.5 hours. The rate of lipid transfer was determined as previously described.s Values are the aver- age of duplicate determinations. BSA, Bovine serum albumin.

many of the other patient groups that were also at increased risk for coronary artery disease (CAD) were shown to have normal rates of transfer to LDL/ VLDL but, interestingly, all of these groups did have significantly reduced transfer to their HDL pool.

The direct effect of the altered lipid composition on the transfer of cholesteryl ester into HDL has been

“Olwne 122 Number 2 HDL composition and cholesteryl ester transport 605

NORMAL HYPERLIPIDEMIA

PERIPHERAL CELLS r---~~

+

--~-., PERIPHERAL CELLS,

FC EFFLUX +

1. CE TRANSFER HD

2. HDL @/(Ii\

MATURAT’oN 6

3. HEPATIC UPTAKE \

@

/

J . .

riliiki$ .---J

L ATHEROMA j

Fig. 5. Reverse cholesterol transport in hyperlipidemia.

demonstrated in incubations utilizing reconstituted HDL (rHDL) of defined compositions8 As rHDL triglyceride content was increased, the recombinant particles became increasingly poorer acceptors of cholesteryl ester transferred by CETP. In addition, increases in free cholesterol had almost the identical effects, markedly reducing the ability of rHDL to receive chalesteryl ester. Increases in either HDL-triglyceride or free cholesterol content were shown to be inversely related to the maximum velocity of lipid transferred to HDL (Fig. 3). This means that cholesteryl ester transfer into HDL is directly affected by its relative content of triglyceride or free cholesterol.

Studies have also shown that variations in HDL apoprotein composition can have profound effects on the transfer of cholesteryl ester into HDL.8 Spherical rHDL prepared from apo A-I or mixtures of purified apoproteins were significantly better acceptors of cholesteryl ester than rHDL prepared from a full complement of HDL apoproteins. In addition, discoidal rHDL prepared from apo A-I were also shown to be better acceptors of cholesteryl esters than discs prepared from apo HDL (Sparks and Pritchard, un- published observation). This indicates that some component of the apo HDL inhibits the catalytic ability of CETP and also that a reciprocal exchange of neutral lipid may not be needed to transfer cholesteryl ester into discoidal HDL. Recent studies in this laboratory have indicated that the lipid transfer inhibitor protein26p 27 is not the only plasma protein capable of regulating CETP activity. We have shown that while some purified apoproteins can also inhibit cbolesteryl ester transfer into HDL, others can markedly stimulate this process (Fig. 4). Both apo A-I and apo E were shown to have a minimal effect on the influx of cholesteryl ester into HDL. Of interest, however, were the observations that apo C-I moderately inhibits cholesteryl ester transfer into

HDL and that both apo A-II and apo C-III2 pro- foundly stimulate this transfer (Fig. 4). While it is unclear to what extent HDL subclass apoprotein composition may be modified in patients with disorders of lipid metabolism, one stu&@ has shown that both ape C-II and apo C-III may be HDL to triglyceride-rich lipop glyceridemia. If this also reduces the abi&y of HDL to receive cholesteryl ester, ~~~~ m apoprotein composition may be additive with the e&&s of increased triglyceride content in reducing the transfer of cholesteryl ester into HDL.

Combined effects of CETP and LCAP. Clearly, the net movement of cholesteryl esters to LDL must also be affected by the rate of cholesteryl eater generation within the HDL pool by the enzyme LCAT. Recent investigations in this laboratorys5 have shown that hyperlipidemic patients with a risk of vascular disease have a significantly incr rata of production of cholesteryl esters in their HDL pool by LCAT. This was shown to be directly related to plasma triglyceride levels but inversely to the level of BDL2n. Reduced HDLz-cholesterol levels have often been observed in patients with b~r~~~~a,30~ 31 and since studies have shown that HRLs may be inhibitory to LCAT,36 it has bean p that the increased e&&cation rates observed in dyslipidemic subjects may be a direct result of reduced inhibition by HDL2. 35 If ahered I-IDL composition promotes increased LCAT action but a defective equilibration of these esters among the HDL particles, the probable consequence is increased transfer and perhaps accumulation of cholesteryl esters in LDL.

Hyperlipidemia and cholestefyl ester *qwMbcstion. Recent evidence suggests that a net transfer of cholesteryl ester into LDL may be a phenomenon of hyperlipidemia rather than a normal physiologic event.

August 1991 606 Sparks, Frohlich, and Pritchard Amsrlcan Hsarl Journal

In postprandial lipemia, triglyceride-rich particles are catabolized by lipoprotein lipase to intermediate and lower density particles that are taken up by the liver.37 Several studies30v31 have shown that in lipemia, whether it be postprandial or dyslipidemic, triglycerides may accumulate in the HDL pool. Ele- vations in HDL-free cholesterol in hyperlipidemic subjects may further promote the accumulation of triglycerides in HDL by inhibiting the action of triglyceride lipases. 37 Elevations in HDL triglyceride content may indirectly reduce apo A-I levels by increasing the fractional catabolic rate of HDL.34* 3g In addition, increased HDL-triglyceride has been shown to impair the interactions between CETP and HDL.* This results in reduced equilibration of cholesteryl esters within hypertriglyceridemic HDL and instead diverts cholesteryl ester to LDL. If this pre- vents the formation of large HDLz-like particles that are inhibitory to LCAT, a reduction in this subfraction may in fact stimulate the production of cholesteryl esters by LCAT. This, combined with im- paired transfer to the HDL pool, may promote a net increased transfer of cholesteryl ester to LDL. Under postprandial conditions this may be a transient phenomenon, designed to effectively deliver cholesteryl ester to liver via the rapidly cleared remnant particles. In dyslipidemia, however, this may markedly change the normal lipoprotein profile and result in the low HDLz levels and higher LDL-cholesterol levels often observed.ly 30, 32

Fig. 5 illustrates the proposed effect of altered HDL composition on the equilibration of cholesteryl ester. Patients with disorders in lipid metabolism often present with elevations in HDL triglyceride and free cholesterol. These changes in HDL composition are associated with a decreased ability of specific HDL subclasses to accept cholesteryl esters transferred by CETP. Defective equilibration of cholesteryl ester within the HDL pool results in reduced HDL cholesterol levels by preventing the maturation and formation of cholesteryl ester-rich HDL:! particles. This may both stimulate the production of cholesteryl esters and result in a net transfer of cholesteryl ester into potentially atherogenic low-density particles. If these particles accumulate as a result of limited hepatic uptake, they may instead be cleared by the scavenger uptake pathway and as such may promote atherogenesis.

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Volume 122 Number 2 HDL composition and cholesterol ester tramport

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33. Ha YC, Barter PJ. Differences in plasma cholesteryl ester transfer activity in sixteen vertebrate species. Comp Biochem Physiol 1982;71b:265-9.

34. Ngoc-Anh Le, Gibson JC, Ginsberg HN. Independent regulation of plasma apolipoprotein C-II and C-III concentrations in very low density and high density lipoproteins: implications for the regulation of the catabolism of these lipoproteins. J Lipid Res 1988;29:669-77.

35. Dobiasova M, Stribrna M, Sparks D, Pritchard PH, Frohlich J. Cholesterol ester&cation in VLDL and LDL depleted plasma: effects of sex and risk factors for coronary artery disease. Arteriosclerosis (In press 1991)

36. Barter PJ. Honkins GJ. Goriatschko L. Jones ME. Comoeti- tive inhibition-of plasma cholesterol esterification by human high density lipoprotein subfraction. 2. Biochim Biochem Acta 1984;793:260-8.

37. Brown MS, Kovanen PT, Goldstein JL. Regulation of plasma cholesterol by lipoprotein receptors. Science 1981;212:628-35.

38. Fielding CJ. Human lipoprotein lipase inhibition of activity by cholesterol. Biochim Biophys Acta 1970;218:221-6.

39. Ginsberg HN, Ngai C, Wang XJ, Ramakrishnan R. Elevated low density lipoprotein production is characteristic of subjects with low plasma levels of high density lipoprotein cholesterol whether they have normal or elevated plasma triglyceride levels [Abstract]. Arteriosclerosis 1990;10:77f>;i.

Seah Nisam, BSEE, Andra Thomas, RN, Morton Mower, MD, and Robert Hauser, MD. St. Paul, Minn.

Cardiac arrest strikes approximately 400,OOO victims annually in the U.S. alone and reaches similar epi- demic proportions in Europe.lT3 The chances of an individual surviving out-of-hospital cardiac arrest unassociated with acute myocardial infarction are at

From Cardiac Pacemakers, Inc.

Received for publication Jan. 23, 1991; accepted March 8, 1991.

Reprint requests: Seah Nisam, BSEE, Cardiac Pacemakers, Inc., 4100 Hamiine Ave. North, St. Paul, MN 55112-5798.

4/l/29749

best about 25 9% .4* 5 Only a few areas, rswh as Miami and Seattle, have developed r~-~~ two-tier ambulance and cardiopulmonary terns, resulting in such impressive “salvage rates.” Importantly, the ratea even in these cities have pla- teaued such that improving upon them appears un- likely, at least in the short tern~*-~ Con&&ring that in most other places, the proba of i3urviving sudden cardiac death @CD) is than one in twenty,7 it is clear that focusing attention and inter- vening in some efficacious manner p~iur to the first

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Lipid transfer proteins, hypertriglyceridemia, and reduced high-density lipoprotein cholesterol