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Technical Briefs |
1
The Curacel Institute of Medical Research, 14/1645 Ipswich Road, Rocklea, Qld 4016, Australia;
2
Lipid Metabolism Laboratory, Department of Surgery, The University of Queensland, Royal Brisbane Hospital, Herston, Qld 4029, Australia;
3
Wesley Medical Centre, Auchenflower, Brisbane, Qld 4060, Australia;
a author for correspondence: fax 61-7-3274 4453
The prime role of cholesterol in the pathogenesis of atherosclerosis is almost universally accepted. Vitamins E and K1, two fat-soluble vitamins associated with lipoproteins, appear to have antiatheroma properties. Paradoxically, there are good linear correlations of vitamins E and K1 with plasma cholesterol concentrations. From an epidemiologist point of view, both vitamins K1 and E could be regarded as being atherogenic. From the point of view of a biochemist, these vitamins may be regarded as antiatherogenic.
Epidemiological studies demonstrate an exponential relationship between increased plasma cholesterol, specifically LDL-cholesterol, and coronary heart disease because of atherosclerosis. Mutations of both the LDL receptor and LDL may be responsible for the loss of recognition between the LDL receptor and the LDL particle, leading to high plasma cholesterol concentrations. Macrophages take up lipoproteins via two receptor-mediated processes, the LDL receptor and a scavenger receptor capable of binding and internalizing various "modified" lipoproteins. The scavenger receptor recognizes apoprotein B-containing lipoproteins that have been modified generally with an increased negative charge. This change may be experimentally induced by acetylation or by reaction with malondialdehyde (1). In vivo peroxidative modifications of apoprotein B produce a series of changes of this apoprotein, which render it recognizable and ingestible by the scavenger receptor (2)(3)(4)(5). This receptor is essentially unregulated, in contrast to the classical LDL receptor, and consequently, pronounced accumulation of cholesteryl ester in macrophages ensues, producing foam cell formation, the hallmark of atheroma (5).
Vitamin E inhibits lipid peroxidation and prevents formation of
malondialdehyde. Independent studies (6)(7) have
shown that modification of LDL by cells that produces increased
susceptibility to oxidation is inhibited by antioxidants such as
vitamin E. Consequently, it may be deduced that vitamin E has
antiatheroma properties. Calcification occurs early in the development
of atherosclerotic plaques. Calcium phosphate (hydroxyapatite)
precipitates by a mechanism similar to active bone formation and is
vitamin K-dependent (8). 
-Carboxyglutamic acid
(Gla)-proteins have been identified in calcified atherosclerotic
plaques. The formation of Gla-proteins is dependent on vitamin K. These
Gla-containing proteins have a very high affinity for hydroxyapatite.
The only known function of these proteins is to bind calcium
(9)(10)(11). It has been suggested that Gla-proteins may be
actively related to atherosclerotic calcification
(11)(12). Decarboxylation of Gla residues to
glutamyl residues greatly diminishes the affinity of Gla-containing
proteins for hydroxyapatite (9)(10)(11). Paradoxically these
Gla-proteins may inhibit precipitation and do not interfere with normal
calcium homeostasis (13). Thus, these proteins may have
opposing roles of facilitator or inhibitor of calcification of plaques
depending on other local factors. Atherosclerotic arteries contain only
~30% of the carboxylase activity formed in healthy arterial segments
(14). Vitamin K, in addition, has antioxidant properties
(15). Thus vitamin K, like vitamin E, appears to have
antiatheroma properties, with vitamin K being a promoter of dystropic
calcification in certain circumstances.
It has been reported previously that concentrations of vitamin E in
serum vary depending on the amount of lipid (16) and
apoproteins (Cham et al., submitted for publication). We now present
further evidence that there are significant correlations between wide
concentration ranges of cholesterol, vitamin E, and vitamin
K1 in serum, which pose some interesting questions.
Concentrations of these components were measured in serum from neonates
and fasting normolipidemic and hyperlipidemic adults. The procedures
used for these human studies were in accord with the Helsinki
Declaration of 1975, as revised in 1993. Serum specimens contained a
wide range of cholesterol (0.8–9.2 mmol/L), vitamin E (0.3–17.7
mg/L), and vitamin K1 (24–910 µg/L) concentrations
(Table 1
). The correlation coefficients derived from the intraclass
correlations pooled over the three groups were as follows: cholesterol
vs vitamin E (r = 0.922, P 
0.001,
n = 57), cholesterol vs vitamin K1 (r
= 0.729, P 0.001, n = 56), and vitamin E vs
vitamin K1 (r = 0.654, P
0.001, n = 56). The three groups of subjects had
significantly different serum concentrations of cholesterol and
vitamins. The significant differences disappeared when vitamin E and
vitamin K1 concentrations were related to total cholesterol
concentrations in serum. The partial correlations between vitamin E and
cholesterol in serum expressed as the ratio vitamin E(µmol/L)/total
cholesterol(mmol/L) ± SD were 3.8 ± 1.4 for neonates, 3.9
± 0.6 for normocholesterolemic adults, and 4.1 ± 0.9 for
hypercholesterolemic patients. The partial correlations between vitamin
K1 and cholesterol in serum expressed as the ratio of
vitamin K1(nmol/L)/total cholesterol(mmol/L) ± SD were
0.13 ± 0.18 for neonates, 0.16 ± 0.08 for normolipidemic
adults, and 0.19 ± 0.06 for hypercholesterolemic patients. We
also present data of a male patient with severe hyperlipidemia who was
treated for this abnormality by diet modification. The extent of the
diet-induced cholesterol changes was linearly related to the extent of
both vitamins E and K1 changes (Fig. 1
). The correlation coefficients derived from the
Marquardt-Levenberg algorithm using SigmaPlot 4.0 curve fitter were as
follows: cholesterol vs vitamin E (r = 0.98,
P 0.001), cholesterol vs vitamin K1
(r = 0.98, P 0.001), and vitamin E vs
vitamin K1 (r = 0.98, P
0.001).
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It would appear from the above data that the variability of the absolute serum vitamin E and Vitamin K1 concentrations may depend on that of the concurrent serum cholesterol concentrations. Accordingly, the assessment of vitamin E and vitamin K1 status should always take into account the lipid concentrations, as has been proposed previously for vitamin E (16)(17)(18)(19)(20). Therefore, statements about the effect on cardiovascular disease of these two vitamins should be done with lipid adjusted values. The current observations highlight some very interesting propositions. On the one hand, because of the observed correlations of vitamins E and K1 with serum cholesterol and because serum cholesterol is related to the incidence of atherosclerosis, from an epidemiologist point of view, both vitamins E and K1 could be regarded as being atherogenic. On the other hand, because of the known biological properties of vitamins E and K as described above, from the point of view of a biochemist, these vitamins may be regarded as being antiatherogenic. From a clinical point of view, these data are confusing because, by reducing serum cholesterol to obtain a more desirable concentration of cholesterol, a concomitant reduction occurs in vitamins E and K, two components that are considered antiatherogenic. What are the clinical implications of these observations?
Acknowledgments
We thank Peter Roeser and Isabelle Delhaize for supervising the dietary manipulation of the patient and for supplying serum from the patient. We gratefully acknowledge the technical assistance of Jack Kamst, John Saville, and Annette Miles. This study was supported in part by a grant from the National Health and Medical Research Council of Australia.
References
The following articles in journals at HighWire Press have cited this article:
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  M. K. Azharuddin, D. St. J. O'Reilly, A. Gray, and D. Talwar HPLC Method for Plasma Vitamin K1: Effect of Plasma Triglyceride and Acute-Phase Response on Circulating Concentrations Clin. Chem., September 1, 2007; 53(9): 1706 - 1713. [Abstract] [Full Text] [PDF]
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B. E. Cham, J. L. Smith, and D. M. Colquhoun What Happens to Vitamin K1 in Serum after Bone Fracture? Clin. Chem., December 1, 1999; 45(12): 2261 - 2263. [Full Text] [PDF]
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