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Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1228-1230
doi: 10.1161/ATVBAHA.107.147082
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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1228.)
© 2007 American Heart Association, Inc.

Editorials

LDL Cholesteryl Oleate

A Biomarker for Atherosclerosis?

Arthur A. Spector; William G. Haynes

From the Departments of Biochemistry (A.A.S.) and Internal Medicine (A.A.S., W.G.H.), Carver College of Medicine, University of Iowa, Iowa City.

Correspondence to Arthur A. Spector, Department of Biochemistry 4-403 BSB, University of Iowa, Iowa City, IA 52242. E-mail arthur-spector{at}uiowa.edu

Cholesteryl esters (CE) are synthesized by 2 enzymes, lecithin:cholesterol acyltransferase (LCAT) and acylCoA:cholesterol acyltransferase (ACAT). LCAT functions in the plasma and forms CE in HDL by transferring polyunsaturated fatty acid from phosphatidylcholine to cholesterol. ACAT, which functions intracellularly, uses fatty acid from acylCoA and forms CE enriched in monounsaturated fatty acid. Two isoforms of ACAT are expressed.1 ACAT1 is present in many tissues and produces the CE that are stored intracellularly, whereas ACAT2 is expressed in the intestine and liver and produces the CE that are secreted in chylomicrons and VLDL.2

See page 1396

In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Bell et al report that ACAT2 gene deletion prevents hypercholesterolemia and atherosclerosis induced by diets containing 10% saturated or monounsaturated fat in a murine model of high LDL apoB100 only, LDL receptor-deleted (LDLr–/–) mice.3 These mice also had larger LDL particle size and hypertriglyceridemia. They attribute the protection of ACAT2 deficiency to a decrease in LDL particles enriched in CE derived from oleate (monounsaturated). When the diet contains large amounts of monounsaturated fats, ACAT2 activity appears to favor production of VLDL particles containing an excessive amount of cholesteryl oleate,4 and these monounsaturated CE remain associated with the lipoprotein particle when it undergoes conversion to LDL. These findings remind us that CE synthesized in the liver can be a source of CE for LDL, a fact that tends to be overlooked because of the current emphasis on the role of the reverse cholesterol transport pathway and cholesteryl ester transport protein (CETP) in supplying CE to VLDL and ultimately LDL. The Figure illustrates how LCAT, CETP, and ACAT2 function to supply monounsaturated and polyunsaturated CE that can accumulate in LDL.


Figure 1
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  		A schematic summary of the pathways that provide cholesteryl esters (CE) for incorporation into LDL. During reverse cholesterol transport, free cholesterol (FC) and phospholipids (PL) released from macrophages form the nascent HDL particles, with most phospholipids containing polyunsaturated fatty acid (PUFA). LCAT transfers PUFA from phospholipids to FC in HDL, forming cholesterol esters containing polyunsaturated fatty acids (CE-PUFA). The CE-PUFA are transferred to VLDL by cholesteryl ester transport protein (CETP), and the CE-PUFA remain associated with the lipoprotein particle during its conversion to LDL. In the endogenous pathway, hepatic ACAT2 uses fatty acyl coenzyme A (CoA) to convert FC to CE. CE formed by this reaction, which contain primarily monounsaturated fatty acid (CE-MUFA), are incorporated into VLDL secreted by the liver and retained in the lipoprotein particle when it is converted to LDL. Mice normally do not express CETP. Therefore, the LCAT pathway is unlikely to be an appreciable source of LDL-CE in the mouse, although there is experimental evidence that LCAT can add CE to LDL if ACAT2 is deficient.4 By contrast, human plasma contains CETP, and the importance of the hepatic ACAT2 mechanism in supplying monounsaturated CE to VLDL and ultimately LDL remains uncertain in humans.7,14

Consistent with the present findings, several previous studies in animal models indicate that ACAT2 and monounsaturated CE promote atherosclerosis. Deletion of the ACAT2 gene prevented atherosclerosis for up to 30 weeks in apoE–/– mice,5 and antisense oligonucleotide-induced inhibition of hepatic ACAT2 protected apoB100 only, LDLr–/– mice against diet-induced hypercholesterolemia and CE deposition in the aorta.6 African green monkeys, which express high levels of ACAT2 in the liver,7 produce LDL enriched in cholesteryl oleate when fed a diet rich in monounsaturated fat, and have equivalent coronary atherosclerosis to those fed saturated fat.8

Taken together, these results indicate that LDL enriched in monounsaturated CE is a risk factor for atherosclerosis and suggest that ACAT2 is a target for treatment of atherosclerosis associated with hypercholesterolemia.9 This is an interesting possibility, but the recent experience with ACAT1 suggests a note of caution. Because ACAT1 is present in macrophages and produces the CE that accumulate in atheroma, it seemed to be a logical therapeutic target. Yet, deletion of ACAT1 gene in mouse models unexpectedly facilitated atherosclerosis,10 apparently by causing apoptosis of the macrophages because of accumulation of unesterified cholesterol in the endoplasmic reticulum.11,12 This mechanism probably accounts at least in part for the disappointing results obtained in recent clinical trials with nonselective ACAT inhibitors, but the possibility that a highly selective ACAT2 inhibitor might have beneficial effects cannot be excluded.13

A key question in assessing the importance of hepatic ACAT2 is the extent to which this mechanism is responsible for LDL-CE accumulation in humans. Although it is generally agreed that ACAT2 is present in the human intestine, there are conflicting data regarding whether ACAT2 is expressed in human liver.7,14 Even the positive report indicates that human hepatic ACAT2 activity is low and variable.7 Therefore, hepatic ACAT2 may not be an appreciable source of LDL-CE in humans. Although the nonhuman primate often is the best experimental model to predict functional significance in humans, such studies will not resolve this issue because the ACAT2 activity in monkey liver is much higher than in human liver.7

Another important issue raised by the findings of Bell et al is whether diets rich in monounsaturated fat may be atherogenic for humans. When the hypercholesterolemic effect of high saturated fat diets was recognized, the initial recommendation was to replace dietary saturated fat with polyunsaturated plant oils rich in linoleic acid. Although this dietary modification is effective in reducing the plasma LDL-cholesterol concentration, further work showed that dietary oleic acid was as effective as linoleic acid in reducing LDL-cholesterol.15 Some subsequent studies have not reproduced this result; for example, higher LDL-cholesterol levels occurred in healthy young men fed a diet rich in olive oil as compared with sunflower oil.16 However, based on a number of additional considerations, the widely held view is that it is preferable to replace saturated fat with monounsaturated rather than polyunsaturated fat. One is that HDL-cholesterol levels are reduced more by a diet rich in polyunsaturated as compared with monounsaturated fat.15 Another is that Mediterranean populations that consume a diet high in olive oil, which contains 80% oleic acid, have relatively low cardiovascular risk factors.17 Still another is the recent evidence that LDL oxidation is a key pathophysiological events in atherosclerosis,18 and there is biochemical data indicating that macrophages and endothelial cells are more sensitive to lipid peroxidation when enriched with polyunsaturated fatty acid than oleic acid.19,20 Although the results reported by Bell et al are derived from a murine model, they should stimulate renewed discussion regarding the relative public health merits of replacing dietary saturated fat with monounsaturated as compared with polyunsaturated fat.

Intriguingly, the findings of Bell et al could provide one potential explanation for the apparent deleterious effects of the CETP inhibitor torcetrapib on atherosclerotic complications. CETP inhibition prevents the transfer of polyunsaturated CE from HDL to VLDL and ultimately LDL. Although LDL CE content decreases after CETP inhibition with torcetrapib,21 LDL content of monounsaturated CE may not be affected because it is derived from hepatic ACAT2, leading to an imbalance between polyunsaturated and monounsaturated CE within LDL. A relative excess of monounsaturated CE in LDL, induced by CETP inhibition, could predispose to atherosclerosis. Conversely, it is possible that low monounsaturated fat intake could prevent the adverse cardiovascular effects of CETP inhibition.

Several additional findings reported by Bell et al deserve comment. First, the trans-monounsaturated fat diet produced the highest total plasma cholesterol concentration and largest aortic CE deposition in ACAT2-expressing mice. This provides additional support for the mounting evidence that diets high in trans-fat increase cardiovascular risk.22 Second, this study also provides fascinating insights into the relative effects of fish- and flaxseed-derived fatty acids on lipids and atherosclerosis. Fish oil was much more effective in reducing cholesterol and monounsaturated CE lipoprotein content than flaxseed-derived {alpha}-linolenic acid, the plant-derived 18-carbon {omega}-3 polyunsaturated fatty acid. In addition, the diet rich in fish oil was much more effective in preventing aortic CE deposition in mice with intact ACAT2 than the diet rich in flaxseed oil. As the authors suggest, this finding may be attributable to poor conversion of {alpha}-linolenic acid to eicosapentaenoic and docosahexaenoic acids by {Delta}6-desaturase. Although this result does not negate the potential nutritional benefit of dietary {alpha}-linolenic acid,23 it suggests that plant-derived {omega}-3 fatty acid supplements are less effective in protecting against atherosclerosis than the longer, more highly unsaturated {omega}-3 fatty acids contained in fish oil. Third, there was an inverse relationship between triglycerides (higher in the ACAT-deficient mice) and atherosclerosis. These results indicate that cholesterol and CE lipoprotein content are critical determinants of atherosclerosis, independent of changes in triglycerides and LDL particle size. Fourth, small LDL (lowest in the fish oil and polyunsaturated diets) was associated with less atherosclerosis, suggesting that use of small LDL particle size as a risk marker is inappropriate without knowledge of LDL CE composition.

Finally, assuming that the LDL cholesteryl oleate content can be shown to be a risk factor for human atherosclerosis, might it become a clinically useful biomarker? This seems unlikely at present because the currently available analytical methods are too cumbersome for routine clinical application. However, automation combined with advances in mass spectrometry may make such an assay practical in the foreseeable future.


*    Acknowledgments
 
Sources of Funding

The authors are supported by research grants R01 HL072845 (to A.A.S.) and PPG HL14388 (to W.G.H.) from the National Heart, Lung, and Blood Institute, National Institutes of Health.

Disclosures

A.A.S. is a member of the Scientific Advisory Boards of Arête Therapeutics and Lipomics Technologies, Inc. W.G.H. has no disclosures.


*    References
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 *References
 

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Related Article:

Dietary Fat–Induced Alterations in Atherosclerosis Are Abolished by ACAT2-Deficiency in ApoB100 Only, LDLr–/– Mice
Thomas A. Bell, III, Kathryn Kelley, Martha D. Wilson, Janet K. Sawyer, and Lawrence L. Rudel
Arterioscler. Thromb. Vasc. Biol. 2007 27: 1396-1402. [Abstract] [Full Text] [PDF]




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