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Circulation Research. 2006;98:431-433
doi: 10.1161/01.RES.0000214406.87060.e0
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(Circulation Research. 2006;98:431.)
© 2006 American Heart Association, Inc.

Editorials

ApoA-I

A Missing Link Between Homocysteine and Lipid Metabolism?

Angela M. Devlin, Steven R. Lentz

From the Nutrition Research Program, Child & Family Research Institute, Department of Pediatrics (A.M.D.), University of British Columbia, Vancouver, Canada; the Department of Internal Medicine (S.R.L.), University of Iowa Carver College of Medicine, and the Veterans Affairs Medical Center (S.R.L.), Iowa City, Iowa.

Correspondence to Steven R. Lentz, MD, PhD, Department of Internal Medicine, C32 GH, The University of Iowa, Iowa City, IA 52242. E-mail steven-lentz{at}uiowa.edu



See related article, pages 564–571


Key Words: cholesterol • homocysteine • lipoproteins

A link between homocysteine and atherothrombotic vascular disease was first suggested by McCully more than 30 years ago.1 The vascular lesions observed by McCully in children with inborn errors of homocysteine metabolism were fibrotic rather than lipid rich, suggesting the possibility that hyperhomocysteinemia may produce vascular pathology through a mechanism independent of altered lipid metabolism. Since that time, many epidemiological studies have confirmed that elevated plasma levels of total homocysteine (tHcy) are associated with an increased risk of coronary events, stroke, and venous thromboembolism.2–4 Most of the epidemiological data indicate that elevation of plasma tHcy is not associated with a significant change in plasma total cholesterol but is negatively associated with high density lipoprotein (HDL) cholesterol.5–7 An effect of homocysteine on HDL metabolism could be clinically important, because HDL protects from vascular disease not only by facilitating reverse cholesterol transport8 but also through its direct antiinflammatory properties.9

During the past decade, the development of animal models has led to rapid progress in defining the pathophysiological consequences of hyperhomocysteinemia in vivo. Experimental approaches to induce hyperhomocysteinemia in animals include the use of diets that are high in methionine and/or low in folate, as well as genetic approaches, such as the generation of knockout mice with targeted disruption of the cystathionine ß-synthase (Cbs),10 methylene tetrahydrofolate reductase (Mthfr),11 or methionine synthase (Mtr)12 genes. Like hyperhomocysteinemic humans, hyperhomocysteinemic animals develop endothelial dysfunction, hepatic lipid accumulation, and decreased plasma HDL cholesterol with minimal changes in plasma total cholesterol.13–15 Hyperhomocysteinemic mice exhibit accelerated atherosclerosis when crossed with apolipoprotein E–null mice.16 Several potential mechanisms for the observed relationship between hyperhomocysteinemia and altered lipid metabolism have been proposed, including: (1) transcriptional upregulation of cholesterol synthesis attributable to effects of homocysteine on hepatic endoplasmic reticulum (ER) stress and activation of sterol regulatory binding proteins (SREBP),13,17 (2) increased plasma levels of very low density lipoproteins (VLDL), thought to be the result of diminished VLDL lipolysis rather than increased hepatic secretion of VLDL,15 and (3) decreased hepatic and serum lecithin-cholesterol acyltransferase (LCAT) activity,15 which could contribute to both reduced HDL cholesterol levels and diminished VLDL lipolysis.

An article by Mikael et al in this issue of Circulation Research sheds new light on the relationship between homocysteine and HDL.18 Using a microarray approach, Mikael et al found that mildly hyperhomocysteinemic Mthfr+/– mice have altered hepatic expression of several genes involved in lipid metabolism, including apolipoprotein A-I (apoA-I), apolipoprotein A-IV (apoA-IV), and cholesterol 7{alpha} hydroxylase (Cyp7A1). The key finding of decreased expression of apoA-I, the major protein component of HDL, was confirmed at the protein level in the liver and plasma of Mthfr+/– mice compared with control Mthfr+/+ mice. A decrease in the plasma level of apoA-I protein was also demonstrated with another murine model of mild hyperhomocysteinemia, the Cbs+/– mouse. A similar decrease in apoA-I levels in Cbs null/apoE null mice was reported recently by Wang and colleagues at the 5th International Conference on Homocysteine Metabolism.19 Mikael et al also observed a significant negative correlation between plasma levels of apoA-I and plasma levels of tHcy in a small cohort of human subjects with coronary heart disease. This finding has yet to be confirmed in large clinical studies.

The work of Mikael et al is a major contribution because it suggests that the decrease in plasma HDL cholesterol in humans and animals with hyperhomocysteinemia is caused, in part, by decreased hepatic expression of apoA-I. The mechanism underlying this potentially pathological effect of hyperhomocysteinemia on apoA-I expression still remains to be worked out. Based on experiments with HepG2 cells, Mikael et al suggest that homocysteine may decrease apoA-I expression through loss of peroxisome proliferator receptor alpha (PPAR{alpha})-mediated apoA-I transcription. This conclusion must be considered provisional, however, because supraphysiological concentrations of homocysteine (5 mmol/L) were needed to demonstrate an inhibitory effect on apoA-I promoter activity. If confirmed, the finding that homocysteine downregulates PPAR{alpha}-induced apoA-I expression would suggest a potential therapeutic approach, especially because ciprofibrate (a PPAR{alpha} agonist) has been shown to protect from endothelial dysfunction in hyperhomocysteinemic mice.20

Some of the effects of homocysteine on the apoA-I promoter observed by Mikael et al appear to be independent of PPAR{alpha}. The transcriptional regulation of apoA-I has been well characterized, with PPAR{alpha} being only one of several factors known to regulate apoA-I expression.21 It is possible, therefore, that homocysteine could affect downregulation of apoA-I transcription through effects on other regulatory factors, such as the transcriptional repressor, apoA-I regulatory protein-1 (ARP-1), or nuclear factor {kappa}B (NF-{kappa}B). Interestingly, inhibition of NF-{kappa}B signaling has been shown to enhance PPAR{alpha}-stimulated expression of apoA-I,22 and high levels of homocysteine are associated with activation of the NF-{kappa}B pathway in extra-hepatic tissues.23,24 The effect of homocysteine on NF-{kappa}B signaling in liver is not known but it seems reasonable to question whether activation of NF-{kappa}B signaling by homocysteine contributes to the transcriptional repression of apoA-I.

Another possible mechanism for decreased apoA-I gene expression in hyperhomocysteinemia may involve changes in DNA methylation. Severe hyperhomocysteinemia in Cbs+/– mice is associated with reduced methylation capacity and gene-specific changes in DNA methylation patterns in liver.25 Methylation of the 5' end of the human gene for apoA-I has been shown to correlate with tissue-specific expression whereby this region is hypomethylated in tissues expressing apoA-I (liver and intestine) and hypermethylated in tissues not expressing apoA-I.26 The apoA-I gene is contained within an apolipoprotein gene cluster on chromosomes 9 and 11 in mice and humans, respectively, that also includes the genes for apoA-IV, apoC-III, and apoA-V. Interestingly, Mikeal et al found that the expression of both apoA-I and apoA-IV was decreased in Mthfr+/– mice, which raises the possibility that elevation of homocysteine leads to altered expression of the entire gene cluster. The role of DNA methylation in governing the expression of this gene cluster in liver is unknown, but it is noteworthy that the cluster contains a CpG-rich region corresponding to the 3' flanking region of the apoA-I gene and the 5'flanking region of the apoA-IV gene. It will be interesting to determine whether the methylation status of this region is altered in hyperhomocysteinemia, perhaps contributing to changes in the expression of both apoA-I and apoA-IV, as well as other genes contained within the cluster.

The work of Mikael et al suggests that altered apoA-I expression may be a critical link between homocysteine and HDL, although additional mechanisms such as decreased LCAT activity15 also may contribute to decreased plasma HDL cholesterol in hyperhomocysteinemia (Figure). If the vasculopathic effects of homocysteine are indeed mediated via decreased expression of apoA-I, the resultant decrease in HDL antiinflammatory activity9 might explain why hyperhomocysteinemia is a risk factor not only for atherosclerosis but also for thrombotic and fibrotic vascular disease, as originally noted by McCully.1 Confirmation of a central role for apoA-I and HDL in the pathophysiology of hyperhomocysteinemia also might help provide an explanation for the failure of several recent clinical trials to demonstrate a benefit of homocysteine-lowering therapy in the secondary prevention of myocardial infarction or stroke,27 because the results of such trials may be confounded by subjects taking statins or other drugs that raise HDL levels.


Figure 1
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  		Schematic representation of the proposed effects of hyperhomocysteinemia on HDL metabolism.


*    Acknowledgments
 
This work was supported by grants from the Office of Research and Development, US Department of Veterans Affairs (S.R.L.), National Institutes of Health grants HL63943 and NS24621 (S.R.L.), American Heart Association grant 0465315Z (A.M.D.), and Hospital for Sick Children Foundation New Investigator grant XG 05-015 (A.M.D.).


*    Footnotes
 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.


*    References
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 *References
 

  1. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol. 1969; 56: 111–128.[Medline] [Order article via Infotrieve]
  2. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. J Am Med Assoc. 2002; 288: 2015–2022.[Abstract/Free Full Text]
  3. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002; 325: 1202.[Abstract/Free Full Text]
  4. den Heijer M, Lewington S, Clarke R. Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies. J Thromb Haemost. 2005; 3: 292–299.[CrossRef][Medline] [Order article via Infotrieve]
  5. Stampfer MJ, Malinow MR, Willet WC, Newcomer LM, Upson B, Ullmann D, Tishler PV, Hennekens CH. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in U.S. physicians. J Am Med Assoc. 1992; 268: 877–881.[Abstract]
  6. Anderson JL, Muhlestein JB, Horne BD, Carlquist JF, Bair TL, Madsen TE, Pearson RR. Plasma homocysteine predicts mortality independently of traditional risk factors and C-reactive protein in patients with angiographically defined coronary artery disease. Circulation. 2000; 102: 1227–1232.[Abstract/Free Full Text]
  7. Qujeq D, Omran TS, Hosini L. Correlation between total homocysteine, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol in the serum of patients with myocardial infarction. Clin Biochem. 2001; 34: 97–101.[CrossRef][Medline] [Order article via Infotrieve]
  8. Lewis GF, Rader DJ. New insights into the regulation of HDL metabolism and reverse cholesterol transport. Circ Res. 2005; 96: 1221–1232.[Abstract/Free Full Text]
  9. Navab M, Anantharamaiah GM, Fogelman AM. The role of high-density lipoprotein in inflammation. Trends Cardiovasc Med. 2005; 15: 158–161.[CrossRef][Medline] [Order article via Infotrieve]
  10. Watanabe M, Osada J, Aratani Y, Kluckman K, Reddick R, Malinow MR, Maeda N. Mice deficient in cystathionine ß-synthase: animal models for mild and severe homocyst(e)inemia. Proc Natl Acad Sci U S A. 1995; 92: 1585–1589.[Abstract/Free Full Text]
  11. Chen Z, Karaplis A, Pai A, Lussier-Cacan S, Rudnicki MA, Rozen R. Generation of MTHFR-deficient mice, an animal model for hyperhomocysteinemia. FASEB J. 1999; 13: A1458.
  12. Swanson DA, Liu ML, Baker PJ, Garrett L, Stitzel M, Wu J, Harris M, Banerjee R, Shane B, Brody LC. Targeted disruption of the methionine synthase gene in mice. Mol Cell Biol. 2001; 21: 1058–1065.[Abstract/Free Full Text]
  13. Werstuck GH, Lentz SR, Dayal S, Hossain GS, Sood SK, Shi YY, Zhou J, Maeda N, Krisans SK, Malinow MR, Austin RC. Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and fatty acid biosynthetic pathways. J Clin Invest. 2001; 107: 1263–1273.[Medline] [Order article via Infotrieve]
  14. Wang H, Jiang X, Yang F, Gaubatz JW, Ma L, Magera MJ, Yang X, Berger PB, Durante W, Pownall HJ, Schafer AI. Hyperhomocysteinemia accelerates atherosclerosis in cystathionine beta-synthase and apolipoprotein E double knock-out mice with and without dietary perturbation. Blood. 2003; 101: 3901–3907.[Abstract/Free Full Text]
  15. Namekata K, Enokido Y, Ishii I, Nagai Y, Harada T, Kimura H. Abnormal lipid metabolism in cystathionine ß-synthase-deficient mice, an animal model for hyperhomocysteinemia. J Biol Chem. 2004; 51: 52961–52969.
  16. Lentz SR. Mechanisms of homocysteine-induced atherothrombosis. J Thromb Haemost. 2005; 3: 1646–1654.[CrossRef][Medline] [Order article via Infotrieve]
  17. Woo CW, Siow YL, Pierce GN, Choy PC, Minuk GY, Mymin D, O K. Hyperhomocysteinemia induces hepatic cholesterol biosynthesis and lipid accumulation via activation of transcription factors. Am J Physiol Endocrinol Metab. 2005; 288: E1002–E1010.[Abstract/Free Full Text]
  18. Mikael LG, Genest J Jr, Rozen R. Elevated homocysteine reduces apolipoprotein A-I expression in hyperhomocysteinemic mice and in males with coronary artery disease. Circ Res. 2006; 98: 564–571.[Abstract/Free Full Text]
  19. Liao D, Tan HM, Hui RT, Jiang XH, Yang F, Li ZH, Durante W, Schafer AI, Chan L, Pownall HJ, Yang XF, Wang H. Hyperhomocysteinemia causes atherogenic HDL metabolism in CBC/ApoE mice. Haematologica Reports. 2005; 1: 26.
  20. Sood HS, Hunt MJ, Tyagi SC. Peroxisome proliferator ameliorates endothelial dysfunction in a murine model of hyperhomocysteinemia. Am J Physiol Lung Cell Mol Physiol. 2003; 284: L333–L341.[Abstract/Free Full Text]
  21. Srivastava RA, Srivastava N. High density lipoprotein, apolipoprotein A-I, and coronary artery disease. Mol Cell Biochem. 2000; 209: 131–144.[CrossRef][Medline] [Order article via Infotrieve]
  22. Morishima A, Ohkubo N, Maeda N, Miki T, Mitsuda N. NFkappaB regulates plasma apolipoprotein A-I and high density lipoprotein cholesterol through inhibition of peroxisome proliferator-activated receptor alpha. J Biol Chem. 2003; 278: 38188–38193.[Abstract/Free Full Text]
  23. Au-Yeung KK, Woo CW, Sung FL, Yip JC, Siow YL, O K. Hyperhomocysteinemia activates nuclear factor-kappaB in endothelial cells via oxidative stress. Circ Res. 2004; 94: 28–36.[Abstract/Free Full Text]
  24. Suhara T, Fukuo K, Yasuda O, Tsubakimoto M, Takemura Y, Kawamoto H, Yokoi T, Mogi M, Kaimoto T, Ogihara T. Homocysteine enhances endothelial apoptosis via upregulation of Fas-mediated pathways. Hypertension. 2004; 43: 1208–1213.[Abstract/Free Full Text]
  25. Devlin AM, Bottiglieri T, Domann FE, Lentz SR. Tissue-specific changes in H19 methylation and expression in mice with hyperhomocysteinemia. J Biol Chem. 2005; 280: 25506–25511.[Abstract/Free Full Text]
  26. Shemer R, Walsh A, Eisenberg S, Breslow JL, Razin A. Tissue-specific methylation patterns and expression of the human apolipoprotein AI gene. J Biol Chem. 1990; 265: 1010–1015.[Abstract/Free Full Text]
  27. Clarke R. Homocysteine-lowering trials for prevention of heart disease and stroke. Semin Vasc Med. 2005; 5: 215–222.[CrossRef][Medline] [Order article via Infotrieve]

Related Article:

Elevated Homocysteine Reduces Apolipoprotein A-I Expression in Hyperhomocysteinemic Mice and in Males With Coronary Artery Disease
Leonie G. Mikael, Jacques Genest, Jr, and Rima Rozen
Circ. Res. 2006 98: 564-571. [Abstract] [Full Text] [PDF]




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